Predictors for cancer treatment

ABSTRACT

The present invention provides methods of predicting a response to a cancer treatment by determining CD68 level or PSMB1 (P11A) polymorphism in a biological sample and the presence or quantity of a second biomarker in the patient. The invention also provides kits and methods for treating cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to provisional application Ser. No. 61/522,596, filed Aug. 11, 2011 and provisional application Ser. No. 61/560,555, filed Nov. 16, 2011, both of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention is related to treatment of cancer patients.

BACKGROUND OF THE INVENTION

While advances in development of successful cancer therapies progress, only a subset of patients respond to any particular therapy. With the narrow therapeutic index and the toxic potential of many available cancer therapies, such differential responses potentially contribute to patients undergoing unnecessary, ineffective and even potentially harmful therapy regimens.

One way to optimize therapy to treat individual patients is to determine whether the patient one or more predictors that correlate with a particular outcome in response to therapy. See, e.g., WO2004/053066; WO2006/133420; WO2008/021183; and WO2009/148528. The ability to predict drug sensitivity in patients is particularly challenging because drug responses reflect both the properties intrinsic to the target cells and also a host's metabolic properties.

There is a need to identify further predictive markers to identify particular cancer patients who are expected to have a favorable outcome when administered particular cancer therapies.

SUMMARY OF THE INVENTION

The invention provides a method for identifying whether a patient has an increased chance for a favorable outcome in response to a cancer treatment, comprising: determining the presence, absence or quantity of one or more predictors in the patient, wherein the presence, absence or quantity of the predictor correlates with at least one favorable outcome.

The presence of predictors may be determined by obtaining a biological sample from said patient. The cancer treatment may comprise administration of a proteasome inhibitor, such as bortezomib. The predictors may be one or more of low CD68, PSMB1 (P11A), PSMB5 (R24C), P65, time since last cancer treatment, one prior treatment, low FLIPI score, age (65 or younger), and low tumor burden.

Also provided are diagnostic kits for identifying patients likely to have a positive outcome in response to a cancer treatment.

The invention also provides methods for treating cancer patients by determining the presence, absence or quantity of one or more predictors in the patient, and selecting a method of treatment dependent on whether the patient is likely to respond to the treatment.

Also provided are uses for proteasome inhibitors for the treatment of cancer, wherein the patients are characterized by one or more of: low CD68, PSMB1 (P11A), PSMB5 (R24C), P65, time since last cancer treatment, one prior treatment, low FLIPI score, age, and low tumor burden.

DESCRIPTION OF THE FIGURES

FIGS. 1-8 show decision trees for determining whether a particular patient will have an increased chance for favorable outcome in response to treatment. “Selected” means that the patient will have an increased chance for favorable outcome in response to treatment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes predictors that serve as useful tools for the prognosis and planning for the treatment of cancer. The predictors are predictive of whether there will be a favorable outcome in response to a particular treatment, for example, treatment with a proteasome inhibitor.

Without limitation, the present invention provides (a) methods for a predicting response to a treatment in a cancer patient by determining presence or quantity of one or more predictors, (b) kits useful in determination of the presence or quantity of the one or more predictors, (c) methods for treating cancer by selecting patients based on presence or quantity of one or more predictors and (d) treating cancer in patients with one or more predictors.

In certain embodiments, a method is provided for predicting response to a cancer treatment (for example, treatment with a proteasome inhibitor such as bortezomib) in a cancer patient comprising determining the presence or quantity of a predictor in a patient or a biological sample from the patient; and wherein the presence or quantity of the predictor is correlated with at least one positive outcome. Certain embodiments comprise determining the presence or quantity of a second predictor in the patient or a biological sample from the patient, wherein the presence or quantity of the second predictor is correlated with at least one positive outcome.

The present invention involves the identification of predictors also referred to herein as “variants”, “markers” “biomarkers” and/or “factors”, that correlate with an increased probability of favorable response to a cancer treatment. The association of patient response to a cancer treatment with these predictors can increase of higher confidence in the safety and/or efficacy with the particular treatment. The predictors may be a gene, protein, patient characteristic, or aspect of the patient history.

Predictors according to this invention which correlate with at least one favorable outcome include low CD68, PSMB1 (P11A) polymorphism, PSMB5 (R24C) polymorphism, P65, age (under 65), one prior treatment, low Follicular Lymphoma International Prognostic Index (FLIPI) score, time since last anti-cancer treatment and low tumor burden. Preferably, the patient has low CD68 or PSMB1 (P11A) and the presence of at least one other predictor. In one embodiment, the patient has low CD68 and PSMB1 (P11A) polymorphism. Predictor pairs according to this invention which correlate with at least one favorable outcome include those shown in Tables 6 and 7.

By “low CD68” is meant that the subject or biological sample from the patient shows less CD68 quantity than the average patient or biological samples from an average patient who has the same disease. In certain embodiments, low CD68 means that 25% or less of the cells in a biological sample express CD68; 50% or less of the cells in a biological sample express CD68; 25% or less of the follicular cells in a biological sample express CD68; 50% or less of the follicular cells in a biological sample express CD68; 25% or less of the perifollicular cells in a biological sample express CD68; or 50% or less of the perifollicular cells in a biological sample express CD68.

By “low FLIPI” score is meant a score of 0 or 1 factor on the Follicular Lymphoma International Prognostic Index (FLIPI score). To determine FLIPI score, one point is assigned to each of: age greater than 60 years, Stage III or IV disease, greater than 4 lymph node groups involved, serum hemoglobin less than 12 g/dL and elevated serum LDH.

As used herein, the terms “comprising”, “containing”, “having” and “including” are used in their open, non-limiting sense.

“Quantity” may mean the value, intensity, concentration, amount, degree, or expression level. For example, quantity of a gene may be the number of times a gene or portion thereof is present in a subject's genome or in the cells of the subject. Quantity may also mean the number of cells in a biological sample expressing a marker, or the overall expression level or intensity of the marker in a biological sample. Quantity may also refer to the number of types or lines of therapy the patient to which the patient may previously been exposed. The quantity may be in comparison to an absolute number, in comparison to a reference sample from a healthy patient, in comparison to an average number from healthy patients, or in comparison to an average number from patients with similar disease.

The cancer treatment may include administration of a single drug or treatment, or a combination treatment comprising administration of more than one drug or treatment. The cancer treatment may be administration of chemotherapy, radiotherapy, or immunotherapy; or the cancer treatment may be a bone marrow transplant.

In certain embodiments, the cancer treatment comprises administering a proteasome inhibitor to a patient. A proteasome inhibitor is any substance which inhibits enzymatic activity of the 20S or 26S proteasome in vitro or in vivo. In some embodiments, the proteasome inhibitor is a peptidyl boronic acid. Peptidyl boronic acids include bortezomib. Proteasome inhibitors include those compounds disclosed in U.S. Pat. Nos. 5,756,764; 5,693,617; 6,831,099; 6,096,778; 6,075,150; 6,018,020; 7,119,080; 6,747,150; 6,617,317; 6,548,668; 6,465,433; 6,297,217; 6,083,903; 6,066,730; 5,780,454; 7,422,830; 7,109,323; 6,958,319; 6,713,446; and 6,699,835. The proteasome inhibitor may be bortezomib.

In certain embodiments, the cancer treatment comprises treatment with anti-cancer agents, including but not limited to, acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminoglutethimide, amsacrine, anagrelide, anastrozole, ancestim, asparaginase, bevacizumab, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cetuximab, cladribine, clofarabine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cyclophosphamide, cytarabine, diclofenac, edelfosine, edrecolomab, eflornithine, emitefur, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, glycopine, heptaplatin, hydroxyurea, ibandronic acid, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole, liarozole, lobaplatin, lonidamine, masoprocol, melarsoprol, melphalan, mercaptopurine, methotrexate, metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, mitomycin, mitoxantrone, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronic acid, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, porfimer sodium, prednisone, raloxifene, raltitrexed, rasburicase, rituximab, romurtide, sargramostim, sizofuran, sobuzoxane, sonermin, steroids, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, ubenimex, valrubicin, verteporfin, vincristine, vinblastine, vindesine, and vinorelbine. In a preferred embodiment, the cancer treatment comprises rituximab. In other preferred embodiments, the cancer treatment comprises melphalin or prednisone, or a combination of melphalin and prednisone.

In certain embodiments, the cancer treatment is a combination treatment. The combination treatment may comprise treatment with a proteasome inhibitor and another cancer treatment or anti-cancer agent. In certain embodiments, the other anti-cancer agent is a monoclonal antibody, e.g., rituximab. In other embodiments, the other anti-cancer agent is melphalin, prednisone, or a combination of melphalin and prednisone.

The favorable outcome may be an overall response rate, overall survival rate, overall complete response rate, duration of response, longer time to next therapy, treatment free interval, positive response to treatment, a longer time-to-progression, longer term survival and/or longer progression-free survival. The favorable outcome may be dose-dependent or dose-independent. The favorable outcome may favorable be in comparison to no treatment, or in comparison to another cancer treatment or cancer treatment(s).

“Cancer” or “tumor” is intended to include any neoplastic growth in a patient, including an initial tumor and any metastases. The cancer can be of the hematological or solid tumor type. Hematologic cancers include such as myelomas e.g., multiple myeloma), leukemias (e.g., Waldenstrom's syndrome, acute myelogenous leukemia, chronic lymphocytic leukemia, granulocytic leukemia, monocytic leukemia, lymphocytic leukemia), and lymphomas (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, malignant lymphoma, plasmocytoma, reticulum cell sarcoma, Hodgkin's disease, non-Hodgkin's lymphoma or follicular B-cell non-Hodgkin's lymphoma). Solid tumors can originate in organs, and include cancers such as brain, skin, lung, breast, prostate, ovary, colon, kidney, and liver. The cancer may be at the primary site, a metastasis, refractory (e.g. refractory to one or more lines of treatment) and/or recurring. In certain embodiments, the cancer is follicular B-cell non-Hodgkin's lymphoma or multiple myeloma.

When the predictor is present within the patient's body, the presence, absence or quantity of the predictor may be assessed by obtaining a biological sample from a patient and determining whether said biological sample contains the predictor or in what amounts the biological sample contains the predictor. A “biological sample” as used herein refers to a sample containing or consisting of tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject. Examples of biological samples include, for example, sputum, blood, blood cells (e.g., white blood cells), amniotic fluid, plasma, serum, semen, saliva, bone marrow, tissue or fine-needle biopsy samples, urine, peritoneal fluid, pleural fluid, and cell cultures. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes. In certain embodiments, the biological sample may be or include tumor cells. Biological samples from a hematological tumor may include bone marrow and/or peripheral blood.

Detection of predictor in a biological sample may be performed by any conventional method for detecting the type of predictor, e.g., direct measurement, immunohistochemistry, immunoblotting, immunoflourescense, immunoabsorbence, immunoprecipitations, protein array, flourescence in situ hybridization, FACS analysis, hybridization, in situ hybridization, Northern blots, Southern blots, Western blots, ELISA, radioimmunoassay, gene array/chip, PCR, RT-PCR, or cytogenetic analysis.

When the predictor is based on a particular genotype or polymorphism, the biological sample may be analyzed by genotyping. The term “genotype” refers to the alleles present in DNA from a subject or patient, where an allele can be defined by the particular nucleotide(s) present in a nucleic acid sequence at a particular site(s). Often a genotype is the nucleotide(s) present at a single polymorphic site known to vary in the human population. “Genotyping” refers to the process of determining the genotype of an individual by the use of biological assays. Current methods of doing this include PCR, DNA sequencing, antisense oligonucleotide probes, and hybridization to DNA microarrays or beads.

A “single nucleotide polymorphism” (SNP, pronounced snip) is a DNA sequence variation occurring when a single nucleotide—A, T, C, or G—in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual). For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case it is said that there are two alleles: C and T. Almost all common SNPs have only two alleles.

The detection of the presence or absence of at least one genotype variance involves contacting a nucleic acid sequence corresponding to one of the genes identified herein or a product of such a gene with a probe. The probe is able to distinguish a particular form of the gene or gene product or the presence or a particular variance or variances, e.g., by differential binding or hybridization.

When the predictor is the presence or quantity (including the expression level) of a particular gene or protein, the presence or quantity (including the expression level) may be determined by immunohistochemistry of a biological sample.

In certain embodiments, a kit is provided for identifying patients who are candidates for a cancer treatment comprising a first reagent for detecting the presence or quantity of one of the predictors of the invention in a biological sample and a second reagent for detecting the presence or quantity of a second predictor of the invention in a biological sample, and instructions for employing the predictors to identify patients who are candidates for the treatment. In certain embodiments, the first reagent detects CD68 quantity and the second reagent detects PSMB1 (P11A) polymorphism or PSMB5 (R24C) polymorphism. The reagents may be antibodies (for example, when testing CD68) or they may be probes or arrays of probes (for example, when detecting gene polymorphism)

In certain embodiments, a method for treating a patient for cancer comprising: determining the presence or quantity of a first predictor in patient or a biological sample from said patient; and determining the presence or quantity of a second predictor in said patient or a biological sample from said patient; and selecting a method of treatment dependent on whether said patient is likely to respond to said treatment.

The invention also provides uses of proteasome inhibitors for the treatment of cancer in a patient, where the patient is characterized by the presence, absence, or quantity of at least one predictor correlated with at least one positive outcome in response to the proteasome inhibitor.

All publications cited herein are hereby incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains.

EXAMPLE 1

Non-Hodgkin lymphoma (NHL) encompasses several unique malignant lymphoid disease entities that vary in clinical behavior, morphologic appearance, immunologic, and molecular phenotype. Follicular lymphoma (FL), the most common indolent NHL, exhibits similar variability with some patients exhibiting very slow disease course while others progress and die within only 5 year (Dave 2004). A randomized, open-label, active-controlled, multicenter, multinational, prospective study to compare the efficacy and safety of the combination of bortezomib and rituximab (Vc-R) to single-agent rituximab in subjects who have relapsed or refractory, rituximab-naive or -sensitive follicular B-cell NHL was performed.

Subjects were centrally randomized to Treatment Groups A (Vc-R) or B (rituximab) in a 1:1 ratio taking into account the following stratification factors:

-   -   Follicular Lymphoma International Prognostic Index (FLIPI) score         (low [0 or 1 factor], intermediate [2 factors], high [≧3         factors]);     -   Prior rituximab therapy (yes, no);     -   Time since last dose of anti-lymphoma therapy (≦1 year, >1         year);     -   Region (United States/Canada, European Union, Rest of World).

Tumor samples for DNA and protein analysis and a blood sample for DNA analysis were collected.

Protein candidates selected were NF-κB (RELA/p65), PSMA5, p27, and CD68. These proteins are attenuated by bortezomib treatment (NF-κB (RELA/p65); PSMA5, p27), regulated by the ubiquitin proteasome pathway (p27), or associated with poor prognosis in lymphoma (CD68). Elevated expression levels of NF-κB (RELA/p65) were associated with longer time-to-progression (TTP) in mantle cell lymphoma (MCL) and in multiple myeloma (Goy 2010, Mulligan 2007, and Keats 2007). Low level expression of PSMA5 was associated with longer TTP in MCL (Goy 2010). Survival analysis in the MCL study also showed that high levels of p27 correlated with better overall survival (OS) (Goy 2010). CD68 was also prespecified and has recently been reported to be a prognostic marker for poor outcome in lymphoma and is also associated with response to rituximab. Candidate genes selected for somatic mutation analysis were Bcl-2 and Notch-1. Other candidates were considered, but were not included because the frequency of the known mutations was less then 10% in the lymphoma setting. Additionally, small amounts of DNA were recovered from collected samples, so the analyses were limited to these two candidates. Bcl-2 has mutation frequencies of 23% in B-cell lymphoma and 50% in follicular lymphoma (Arif 2009) and Notch-1 has a mutation frequency of 24%. Bcl-2 is an important anti-apoptotic protein frequently over expressed in aggressive lymphomas and previous reports have suggested that bortezomib overcomes Bcl-2-mediated protection (Fischer 2005, Yin 2005, Yeung 2006, Mitsiades 2002 and Wojcik 2002). Notch-1 has been shown to increase the residence time of NF-κB (RELA/p65) in the nucleus (Shin 2006). This acts in direct opposition to bortezomib, which prevents NF-κB from reaching the nucleus by inhibiting proteasomal degradation of I-kappa-B proteins, whose role is to retain NF-κB in the cytoplasm. Notch 1-mediated increased residence time of NF-κB in the nucleus activates the transcription of the cell cycle regulators, eg, cyclins D1 and D2, which may contribute to the up-regulation of genes involved in immune and inflammatory processes (Karin 2002). Mutations found in functional sequences of these two genes were hypothesized to contribute to inter-individual responses to treatment with bortezomib.

Drug target candidate genes were included for both bortezomib (PSMB1, 2, 5, 6, 8, 9) and rituximab (FCGR2A, FCGR3A). The chemical structure of bortezomib interacts with PSMB subunits 1, 2, and 5 and there is documented evidence of polymorphisms in these subunits as well as in PSMB6, 7, and 8. Polymorphisms within the subunits may affect the ability of the drug to bind effectively or may prevent autocatalytic processing of pro-sequences that could lead to variability in levels of proteasomes and/or response to bortezomib in individual patients. For rituximab, the presence of single nucleotide polymorphisms (SNPs) corresponding to phenotypic expression of valine (V) or phenylalanine (F) at amino acid 158 of FCGR3A and of histidine (H) or arginine (A) at amino acid 131 of FCG2A greatly influences the affinity of IgG for the Fcγ receptor (Binstadt 2003, Wu 1997). Expression of the high-affinity V allele at 158 results in tighter binding of FCG3A to IgG1 and IgG3, whereas the low-affinity F allele is associated with decreased binding of FCG3A to IgG. Similarly, the high-affinity H allele at 131 results in greater affinity of FCGR2A for IgG2, whereas the low-affinity A allele correlates with decreased binding. Correlation of these low-affinity polymorphisms has been associated with worse clinical response and progression-free survival (PFS) after rituximab therapy in studies of NHL (Cartron 2002). Therefore, we examined whether subjects with these polymorphisms were responsive to treatment with Vc-R as this may be an alternative therapy for patients with limited treatment options.

The exploratory objectives in this study were to identify patient populations who were more or less likely to respond to Vc-R or rituximab alone by:

-   -   Performing association analyses of CD68, NF-κB (RELA/p65),         PSMA5, and p27 protein expression levels with selected clinical         study endpoints     -   Performing association analyses of Notch-1 and Bcl-2 somatic         mutations (single and in combination) with selected clinical         study endpoints     -   Performing association analyses of FCGR2A and FCGR3A         polymorphisms (SNPs) with selected clinical study endpoints     -   PSMB1, PSMB2, PSMB5, PSMB6, PSMB8, and PSMB9 polymorphisms         (SNPs) with selected clinical study endpoints     -   Performing combinations of biomarkers with selected clinical         study endpoints.

Multiple testing corrections were done using the false discovery rate (FDR) method for pair-wise comparisons and by forward selection when multiple biomarker combinations were compared. In practical terms, the FDR is the expected proportion of false positives; for example, if 1000 observations were predicted to be different, and the FDR for these observations was 0.10, then 100 of these observations would be expected to be false positives. Over-fitting is controlled by cross validation and independent validation within the analysis.

Genes with sufficient variation include:

FCGR2A (H166R, Q62R, Q62X)

FCGR3A (V212F)

PSMB1 (P11A)

PSMB5 (R24C)

PSMB8 (G8R)

PSMB9 (R60H, V32I)

PSMA (positive nuclear and cytoplasmic staining)

CD68 (overall positive, positive follicular, positive peri-follicular)

P27 (nuclei positive, intensity score)

RELA/p65 (positive nuclear and cytoplasmic staining, intensity score).

The intent-to-treat (ITT) population was defined as all subjects who were randomized. Subjects in this population were analyzed according to the treatment to which they were randomized. Biomarker evaluations were done on this population when biomarker data was generated for the clinical study endpoints.

Protein marker expression levels (CD68, NF-κB (P65), PSMA5, P27) were determined by immunohistochemistry (IHC). The expression level cut-points for single-marker analyses were:

CD68:

% positive follicular (0-25, 26-50, 51-75, >75),

% positive peri-follicular (0-25, 26-50, 51-75, >75),

overall % positive (0-25, 26-50, 51-75, >75)

NF-κB (p65):

% positive cytoplasmic signal (<90%, >91% cutoffs),

% positive nuclear signal (0, <5%, >5%)

Nuclear staining intensity (<1+, >2+)

PSMA5:

% positive cytoplasmic signal (0-20, 30-50, 60-70, 80-90)

% positive nuclear signal (0-20, 30-50, 60-70, 80-90)

Cytoplasmic staining intensity (<2+, 3+)

Nuclear positive vs. all other

P27:

% positive nuclear staining (0-20, 30-50, 60-70, 80-100)

Nuclear signal intensity (<1+, >2+)

Cut-points selected for pair-wise comparisons were chosen to reduce the total number of comparisons that would be done. The selected cut-points are found in Table 1:

TABLE 1 Cut-Points for Protein Markers Included in the Pair-Wise Comparisons Protein Marker Cutoff 20S (PSMA5) % nuclear staining ≦20 vs. >20 20S (PSMA5) % positive cytoplasmic signal ≦90 vs. >90 20S intensity cytoplasmic signal ≦2+ vs. >2 CD68 overall positive ≦50 vs. >50 CD68 positive follicular ≦50 vs. >50 CD68 positive perifollicular ≦50 vs. >50 P27 % nuclei positive ≦70 vs. >70 P27 signal intensity ≦1+ vs. >1 P65 (NF-κB) % nuclear staining 0 vs. >0 P65 (NF-κB) % positive cytoplasmic signal ≦90% vs. >90% P65 (NF-κB) intensity cytoplasmic signal ≦1+ vs. >1

Germline SNP data for PSMB subunits and FCGR2A and FCGR3A genes were generated by standard polymerase chain reaction (PCR) methodologies. Alleles detected in these assays are found in Table 2:

TABLE 2 Alleles for PSMB Subunits and FCGR2A and FCGR3A Genes FCGR2A FCGR3A PSMB1 PSMB2 PSMB5 PSMB6 PSMB8 PSMB9 H166R D118N A171S E49X L206M A234D G8R G9E (aka H131R) P273L D183G 1208N G187V R24C P107A R141C R60H Q62R E63V P11A L159F — — V182M V32I Q62X H194Y P193L — — — — — V217I L102R — — — — — — — L281F — — — — — — — R270X — — — — — — — S231A — — — — — — — S72R — — — — — — — V142I — — — — — — — V212F — — — — — — (aka V158F)

The following clinical endpoints were included in the analysis within each treatment group and an overall comparison was made with the biomarker-related endpoints: Progression-free survival, defined as the interval between the date of randomization and the date of progressive disease (PD) or death, whichever is first reported in the ITT population; overall survival; overall response rate (complete response [CR]+CR unconfirmed [CRu]+partial response [PR]); overall CR rate (CR+CRu); duration of response; time to next anti-lymphoma therapy; and treatment free interval.

Subjects from who met all of the following criteria were included in the analysis: subjects in the ITT population; subjects with evaluable biomarker data determined by IHC- or PCR-based methodologies; and subjects with clinical data for at least one of the clinical endpoints listed above.

The primary biomarker analysis was aimed at identification of differentially expressed proteins, mutations, or genotypes that were associated with clinical study endpoints. Covariates included in the analysis were: FLIPI score (low [0 or 1 factor], intermediate [2 factors], high [≧3 factors]); prior rituximab therapy (yes, no); time since last dose of anti-lymphoma therapy (≦1 year, >1 year); region (United States/Canada, European Union, Rest of World), age, sex, race, Ann Arbor stage (I, II, III, IV), Number of prior lines of therapy (1, 2 and more), and high tumor burden (yes, no).

For single-marker association analyses and pair-wise comparisons, a log rank test and Cox proportional hazard model was utilized for assessments of PFS, TTP, and OS between the treatment groups. Kaplan-Meier curves were utilized to estimate the distribution differences between groups in the time-to-event analyses. Comparison of the response rates between the treatment groups was conducted using the Fishers exact test. Single-marker association analyses were stratified by the covariates.

For pair-wise comparison analysis, biomarker pairs were formed by combinations of two markers. A log rank test was utilized for assessments of PFS, TTP, and OS between the treatment groups in the subpopulation defined by biomarker pairs. Kaplan-Meier curves were utilized to estimate the distribution differences between groups in the time-to-event analyses. Comparison of the response rates between the treatment groups was conducted using the Fishers exact test. Methods of Analysis for the multiple biomarker comparison models can be found in section 4.6.

For each analysis, demographic and baseline characteristic variables were to be summarized for the biomarker population as follows. Descriptive statistics (mean, standard deviation, median, and range) were calculated for baseline demographic data (including: age (year), age category (>65 years and ≦65 years), sex (male, female), race (White, Asian/Pacific Islander, and Black/Other), FLIPI score (low [0 or 1 factor], intermediate [2 factors], high [≧3 factors]); prior rituximab therapy (yes, no); time since last dose of anti-lymphoma therapy (≦1 year, >1 year); Ann Arbor stage (I, II, III, IV), number of prior lines of therapy (1, 2 and more), high tumor burden (yes, no), and region (United States/Canada, European Union, Rest of World) and were compared with summary statistics from the clinical trial data sets.

The stratified log rank test and Cox proportional hazard model was utilized for assessments of PFS between the treatment groups. The Kaplan-Meier method was to be used to estimate the distribution of overall PFS for each treatment group in the biomarker population, and overall; stratified by expression level, SNP, or mutation (or covariate groups as noted above). The hazard ratio and 95% confidence interval was based on a stratified Cox's proportion hazard model with treatment as the explanatory variable. Analyses were done for the population overall and by treatment group, and each of these analyses were also stratified by the following factors if sufficient sample size existed:

FLIPI score (low [0 or 1 factor], intermediate [2 factors], high [≧3 factors])

Prior rituximab therapy (yes, no)

Time since last dose of anti-lymphoma therapy (≦1 year, >1 year)

Region (United States/Canada, European Union (Belgium, Czech Republic, Finland, France, Germany, Great Britain, Greece, Hungary, Italy, Poland, Portugal, Slovakia, Spain, and Sweden), Rest of World (Argentina, Australia, Brazil, India, Israel, Mexico, China, Korea, Romania, Russia, South Africa, Thailand, and Ukraine)) Age (<65, >65) Sex Race Ann Arbor stage (I, II, III, IV) Number of prior lines of therapy (1, 2 and more) High tumor burden (yes, no)

Overall Survival was measured from the date of randomization to the date of the subject's death. If the subject was alive or the vital status was unknown, it was censored at the date that the subject was last known to be alive. Similar to PFS and TTP, the Cox proportional hazard model was used to evaluate the association between biomarker endpoints and OS. Kaplan-Meier survival curves were presented. Analyses were done for the population overall and by treatment group, and each of these analyses was stratified by the covariates used for PFS.

Comparison of the response rates between the treatment groups was conducted using the Fishers Exact Test. Duration of response, time to response, and time to clinical relapse were analyzed descriptively, where appropriate, and the biomarker subset was compared (if appropriate, determined as per the initial analysis) to the overall clinical cohort, by treatment group and overall. An exploratory estimate of the response rates in each treatment group was presented with 2-sided 95% confidence intervals. The number and percentage of subjects falling into each response category was descriptively tabulated.

Analyses were done for the population overall and by treatment group. Each of these analyses were stratified by the same covariates utilized for PFS assessment.

Further analyses were planned because of the number of pair-wise comparisons that were significant prior to FDR corrections and because these pairs selected unique individuals with longer PFS and a trend for longer survival. These analyses sought to identify a single biomarker classifier that selected for a large PFS benefit and an OS benefit (or trend) with a high population frequency. The dataset was utilized whereby discovery and confirmation test sets within the same population were defined. The study was conducted as follows:

Subjects with no missing biomarker values (n=354) were assigned in a ratio of 7:3 into a discovery and confirmation set using simple randomization. The balance demographic factors and clinical covariates listed previously were confirmed using either the t-test or Mann-Whitney test. The discovery set (67%) was used for identification of biomarkers with significant association with PFS; subjects included had no missing biomarker data. The confirmation set (33%) was used for independent validation. Subjects with missing data were included in the confirmation dataset provided that significant biomarker data identified in the discovery phase was available. Additionally, evaluable sample from China were also included in the confirmation set.

As in the initial analyses, if all subjects have the same protein expression level for a particular biomarker, that biomarker was removed from the analysis. If all subjects had the same mutation, no mutation, or 1 mutation level represented 90% of the samples, then either that mutation or that gene was removed from the analysis.

In the discovery phase of biomarker combination analysis, all subjects that had missing values for any biomarker specified in Section 2 were excluded. Samples with missing data were included in the confirmation set provided that the missing data was not part of the associated dataset. Samples with missing biomarker data were considered “unevaluable” and were excluded from the confirmation set, all other samples not used in the discovery set were included in the confirmation set.

Biomarker outliers were not removed from the analysis.

Demographic and baseline covariates were to be compared using the t-test or Mann-Whitney test to ensure that there were no statistically significant differences between the discovery and confirmation sets. Demographic and baseline characteristics were to be summarized for the discovery and confirmation sets and overall. Subjects excluded in the final analysis were not to be evaluated in this data comparison. Descriptive statistics (mean, standard deviation, median, and range) were to be calculated for the baseline demographic data and comparison between the demographic and test set were to be made to ensure there were no significant differences between them.

Covariates included in the analysis were: FLIPI score (low [0 or 1 factor], intermediate [2 factors], [≧3 high factors]); prior rituximab therapy (yes, no); time since last dose of anti-lymphoma therapy (≦1 year, >1 year), age, Ann Arbor stage (I, II, III, IV), Number of prior lines of therapy (1, 2 and more), high tumor burden (yes, no), region (United States/Canada, European Union, Rest of World), sex, and race.

All markers and covariates were to be treated as categorical variables in the analysis. Protein biomarkers were to be dichotomized. The cut-points for protein markers were to be optimized based on enrichment of responders vs. non-responders and reasonable population size. Specifically, for each biomarker, number of responders and non-responders (based on overall response) and their percentages in the evaluable population were to be determined using every potential cut-point listed in the Table 3. Summary tables with potential cut-points, number of responders, number of non-responders, and their percentages were to be generated for each biomarker.

TABLE 3 Response by Cut-Point (Evaluable Population) Protein Marker Cutoff 20S (PSMA5) % nuclear staining 20%, 50%, 70%, 90% 20S (PSMA5) % positive cytoplasmic signal 20%, 50%, 70%, 90% 20S intensity cytoplasmic signal 0, 1, 2 CD68 overall positive 25, 50, 75, 90 CD68 positive follicular 25, 50, 75, 90 CD68 positive perifollicular 25, 50, 75, 90 P27 % nuclei positive 20%, 50%, 70%, 90% P27 signal intensity 0, 1, 2 P65 (NF-κB) % nuclear staining 0, 1, 5, 10, 20 P65 (NF-κB) % positive cytoplasmic signal 20%, 50%, 70%, 90% P65 (NF-κB) intensity cytoplasmic signal 0, 1, 2

All genotypes were to be considered separately in the analysis (eg, C/C, C/T, T/T):

FCGR2A (H166R, Q62R, Q62X)

FCGR3A (V212F)

PSMB1 (P11A)

PSMB5 (R24C)

PSMB8 (G8R)

PSMB9 (R60H, V32I).

Evaluation and Ranking of Single-Marker Associations with PFS (Discovery set)

The initial step of the analysis was selection and ranking of markers that were to be used in subsequent multiple comparison analysis. All protein, SNPs with greater than 10% genotype variability, and clinical covariates listed were to be included as categorical variables. The evaluation was to include the following steps: Biomarkers (including clinical covariates) that showed improvement of PFS from prior single-marker association analysis (p<0.2) were reported. Only analyses that were done using IRC review were used. Each biomarker and clinical covariate was evaluated by Cox regression to assess the importance of biomarkers with respect to PFS. The P-values and weights/odds ratios of all markers in the Cox model were reported. To evaluate correlation among biomarkers, a pairwise correlation matrix was generated using Spearman correlation method. Biomarkers that showed high correlation (p<0.05 and correlation coefficient >0.7) were highlighted. Markers that had high correlation were re-analyzed in a Cox regression model with their interaction terms.

An interim summary of this analysis was generated for selecting markers that were used in multiple comparison analysis. The markers that were selected were based on the following criteria:

Relatively lower P-values in Cox regression for marker effect on PFS.

PFS benefit in Vc-R arm compared to R arm that were based on interaction with treatment in Cox regression or single marker logrank tests.

If multiple markers are highly correlated and have high ranks from Cox regression, representative marker(s) that have the highest rank from Cox regression with interaction terms were used. Subpopulations of samples showing a large PFS benefit in Vc-R arm compared to the R arm were to be identified by an exhaustive search of “AND” combination of biomarkers. Specifically, subpopulations of patients were formed from “AND” combinations of any two or three biomarkers selected in section 4.6.1. The difference of PFS for the patient subsets defined by the markers was evaluated using the log-rank test with PFS as response variable and 5-fold cross-validation as described below.

The discovery set was randomly split into 5 subsets with 20% of subjects in each subset. An 80% subset was formed by combining 4 of the 5 subsets. Using the 80% subset, subpopulations of patients were formed from “AND” combinations of biomarkers. If the number of samples (N) in either Vc-R or R is <5 for the subpopulation, the subpopulation was skipped. For subpopulations with N≧5 in both arms, the difference in PFS for the patient subsets defined by the two markers was evaluated using the log-rank test. A looser P-value cutoff was applied because of the exploratory nature of this analysis. The PFS benefit was subsequently tested on the remaining 20% subset.

The remaining 4 cross validation sets were tested similarly (P value cutoff was not applied due to small sample size). Specifically, a different 20% subset from above and a new 80% subset formed with remaining subjects was used to repeat logrank tests until all 5 20% subsets were tested. The proportion of iterations with large PFS benefit in both 90% subset and 10% subset were reported.

Biomarker combinations were merged and evaluated again for PFS benefit and statistical significance with cross validation. For subpopulations formed from merging of marker combinations, if the size of the subpopulation is ≦10% of the discovery set, no statistical test will be performed. Exhaustive merging of marker pairs and assessment of PFS benefit was performed. Only marker combinations or merging of marker combinations that were significant were reported to save computational time. Results were saved after each iteration.

For top ranked marker combinations, decision rules for defining selected patient subpopulations were established using Classification and Regression Tree. Association of the selected patient subpopulations for other clinical endpoints was also evaluated. Performance of PFS and OS in the confirmation set was evaluated by testing the association of biomarkers identified in the discovery set using the decision rules defined. The PFS of both biomarker positive and negative subgroups was reported for both study arms in the confirmation set. P-value cutoff was not applicable due to a small sample size, but was still reported.

Samples included in the independent confirmation set may have missing values for biomarkers not found to associate with PFS, however, subjects who could not be classified due to missing values of the selected biomarkers were regarded as “unevaluable” and were excluded.

Initial analyses focused on single-marker associations stratified by covariates. Significant associations were found in the single marker association analysis including CD68, PSMB1 (P11A), P65 and PSMB5 (R24C). Subsequent pair-wise analysis identified a biomarker pair with significantly longer PFS and a trend for an OS benefit. Because there were no data sets available for independent confirmation of this finding, dataset was split into the Discovery and Confirmation sets described above. As part of that analysis, multiple biomarker combinations were compared and other significant combinations were identified. The association deemed to be most clinically appropriate from all analyses was the PSMB P11A heterozygote in combination with CD68 Low (0-50%) expression. Sub-populations of clinical interest are subjects with high tumor burden, prior rituximab and one or two prior lines of therapy.

Pair-wise combinations of markers were conducted using the stratified log rank test for each potential pair to determine differences in PFS between the Vc-R and rituximab only treatment groups. One-hundred and two biomarker pairs had a log rank p<0.05. Of these, 97 pairs had a >1% population frequency. Fourteen pairs also showed a PFS improvement of ≧6 months. In this analysis, 1,140 pair-wise comparisons were made (covariates were paired with each individual marker to supplement the analyses). Following FDR correction, 1 pair was significant (FDR=0.051). This biomarker pair identified 33% of the biomarker evaluable population that had a 7.5 month PFS advantage when treated with Vc-R compared with rituximab alone (Table 4) and a trend for better OS (p=0.055, HR: 0.426 [0.174, 1.046] This pair is composed of PSMB1 P11A (C/G heterozygote) and CD68 Low expression defined as 0-50 positively stained cells. Following, this pair will be referred to as the biomarker positive subgroup. The biomarker negative subgroup does not have this biomarker pair and has a different PSMB1 genotype and CD68 expression level.

TABLE 4 Comparison of Biomarker Positive Population With Biomarker Negative Population for PFS and OS Biomarker Positive Biomarker Negative Total (N = 118) (N = 238) (N = 356) Vc − R Rituximab Vc − R Rituximab Vc − R Rituximab PFS N 57 61 118 120 175 181 Median (months) 16.6 9.1 12.5 12.5 13.6 11.3 95% CI (0.26-0.639) (0.759-1.425) (0.621-1.032) p-value 0.0001 0.8097 0.0855 HR 0.407  1.04  0.801  OS N 57 61 118 120 175 181 Median (months) NA NA NA NA NA NA 95% CI (0.174-1.046) (0.617-1.658) (0.527-1.239) p-value 0.0550 0.9645 0.3270 HR 0.426  1.011  0.808  Biomarker positive = PSMB P11A heterozygote and CD68 “Low” biomarker pair, Biomarker negative = all subjects without this pair, Vc − R = Bortezomib + Rituximab, PFS = progression free survival, OS = overall survival, CI = confidence interval, HR = hazard ratio

Importantly, biomarker positive subgroup (PSMB1 P11A heterozygote and CD68 Low expression) also had a significantly better overall response rate 73.7% for those treated with Vc-R compared to 47.5% with R alone (p=0.0077), and a longer time to next treatment (p=0.0013) and duration of treatment free interval (p=0.0017).

Similar AE profiles were observed in the biomarker positive and biomarker negative populations. Similar treatment exposure was observed in the biomarker positive and biomarker negative populations. Subjects treated with rituximab in the biomarker positive population had a median dose of 2941 mg/m² compared to 2940 mg/m² in the biomarker negative population. Subjects treated with Vc-R in the biomarker positive population had a median dose of 31.1 mg/m² compared to 30 mg/m² in the biomarker negative population. Total number of doses, duration of exposure, dose intensity, relative dose intensity and maximum number of cycles received also showed very similar differences.

Subjects treated with Bortezomib+rituximab maintained longer PFS when biomarker positive and stratified by any FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race. In patients with higher risk and poor prognosis, e.g. high tumor burden, medium or high FLIPI, older than 65, or with prior rituximab treatment, greater PFS improvement were observed in patients when biomarker positive comparing to when biomarker negative. Longer PFS was maintained regardless of time from last treatment or number of previous treatments by prior rituximab or by number of rituximab treatments less than or equal to 2.

Subjects treated with Bortezomib+rituximab maintained longer overall survival when biomarker positive and stratified by FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race. Subjects treated with Velcade+rituximab maintained longer PFS when positive for CD68 low (0-50) and stratified by any FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race. When CD68 high, they did better on rituximab alone as expected. Subjects treated with Velcade+rituximab maintained longer PFS when positive for PSMB P11A heterozygote and stratified by any FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race. When CD68 high, they did better on rituximab alone as expected.

A trend for a longer OS was found for biomarker positive subjects (p=0.055, HR 0.426. When the biomarker contributions are examined individually, this trend is less distinguishable. For subjects that are PSMB1 P11A C/G heterogygotes, the significance is p=0.2525 and HR=0.673 while subjects that are CD68 positive (0-50), the significance is p=0.0714 and HR=0.615.

Subjects treated with Velcade+rituximab had a trend for better OS when positive for CD68 low (0-50) and stratified by any FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race. Subjects treated with Velcade+rituximab had a trend for better OS when positive for PSMB1 P11A heterozygote and stratified by any FLIPI score, by tumor burden, by Ann Arbor score, by age, by region, by sex, and by race.

Following cross validation, the pair previously described (CD68 Low and PSMB P11A) was found to be significant in the smaller discovery cohort (p=0.0003, 14.2 months for Vc-R vs 8.5 months for R, HR=0.4 (0.24, 0.67)). There was still a trend for longer OS in the biomarker positive population (p=0.1291), HR=0.47(0.17, 1.27). Although the number of subjects in the confirmation cohorts is small, the positive trend in both PFS and OS was found to be maintained. In confirmation cohort 1 (n=106), subjects treated with Vc-R had approximately 18.2 mo PFS while those treated with R alone had 9.5 months PFS (p=0.0817, HR=0.44). In confirmation cohort 2 (n=426), subjects treated with Vc-R had 13.9 months median PFS while those treated with R had 9.5 months median PFS (p=0.0878, HR=0.49). The trend in OS was also maintained

It was of interest to determine the individual contributions of each biomarker to the PFS benefit found in subjects with both biomarkers (PSMB1 P11A heterozygote and CD68 Low). Within the biomarker positive population, subjects with PSMB1 P11A (C/G) had 16.6 months median PFS when treated with Vc-R compared to 9.5 months median PFS when treated with R alone, showing a 7.1 month PFS advantage when the combination was used. This benefit was not seen in biomarker negative subjects with Vc-R. Consistent with prior publication on CD68 and rituxan, this study shows that subjects with higher CD68 expression do better on rituximab alone (16.2 months median PFS) than those with lower CD68 expression (9.3 months median PFS). However, these subjects with low CD68 (0-50) had significantly longer PFS (14 months median) when treated with the combination compared to similar patients treated with R alone (9.3 months median); this is a 4.7 month PFS advantage (HR=0.64 (95% CI: 0.475-0.864).

These results suggest that patient subgroups can be identified prior to therapy that have significantly longer PFS and a trend for better OS when treated with combination Vc-R compared to R alone. One biomarker pair that maintains significance after multiple comparison corrections (FDR=0.051) includes a proteasomal subunit SNP [PSMB1 P11A heterozygote] and CD68 with low (0-50) expression. Three hundred fifty six subjects were evaluable for both of these biomarkers within this study. Additionally, this biomarker pair had a high population frequency with approximately one third of the evaluable subjects having both of these biomarkers. Subjects with this biomarker pair had a longer PFS interval when treated with Vc-R (16.6 months) compared to rituximab alone (9.1 months) demonstrating a PFS benefit of approximately 7.5 months with the combination. This group also appears to have an OS benefit with Vc-R that clearly trends toward significance (HR: 0.426 (0.174-1.046) P=0.0550), a higher ORR (73.7% on Vc-R vs 47.5% on rituximab alone, p=0.0077), a longer time to next treatment interval (33.1 mo on Vc-R vs 14.8 mo on rituximab alone, p=0.0013) and a longer duration of treatment free interval (27.8 mo vs 10.1 mo, p=0.0017).

Importantly, the CD68/PSMB P11A biomarker positive cohort was representative of the overall trial population with regard to demographics and clinical characteristics. Of note, approximately half of this cohort was represented by subjects with high risk disease and poor prognostic features. In patients with higher tumor burden (˜54%), medium or high FLIPI (˜76%), older age (>65) (˜25%), with prior Rituximab treatment (˜46%), or with two (˜26%) or more than two (˜30%) lines of prior therapy the PFS benefit of the CD68/PSMB P11A biomarker positive cohort appears to be maintained. These patients are generally regarded as “high risk” with limited treatment options and these preliminary findings suggest that biomarker positive subjects with high risk features may benefit from Vc-R.

Polymorphisms in PSMB1 and PSMB5 were found to have significant associations with clinical endpoints as single markers. The combination of PSMB1 [P11A] with CD68 was found to be synergistic and present in a high proportion of the study cohort. PSMB1 P11A is a polymorphism found in the leader sequence of the proteasome PSMB1 gene (Chen 1996). The leader sequence is responsible for appropriate subunit assembly and it has been reported that alterations of charged amino acids reduces the efficiency of subunit assembly (Schmidt 1999). Once assembled autocatalysis allows removes the leader sequence. The second biomarker in the pair is CD68 expressing tumor infiltrating macrophages. Previous reports have shown that high levels of CD68 associate with better response to rituximab (Taskinen 2007).

Importantly, this study has shown that subjects with low levels of CD68 expression have longer PFS and better overall response to Vc-R compared to R alone especially when present with PSMB1 P11A heterozygote as discussed above. Following cross validation, the pair previously described (CD68 Low and PSMB P11A) was found to be significant in the smaller discovery cohort (p=0.0003, 14.2 months for Vc-R vs 8.5 months for rituximab alone, HR=0.4 (0.24, 0.67)). There was still a trend for longer OS in the biomarker positive population (p=0.1291), HR=0.47(0.17, 1.27). Although the number of subjects in the confirmation cohorts was small, the positive trend in both PFS and OS was found to be maintained. In confirmation cohort 1 (which excludes subjects from China; n=106), subjects treated with Vc-R had approximately 18.2 mo PFS while those treated with R alone had 9.5 months PFS (p=0.0817, HR=0.44). In confirmation cohort 2 (which includes China subjects and subjects with missing data; n=126), subjects treated with Vc-R had 13.9 months median PFS while those treated with R had 9.5 months median PFS (p=0.0878, HR=0.49). The trend in OS was also maintained.

EXAMPLE 2

Single predictors which correlated with a positive response are shown in Table 5.

TABLE 5 Single predictors. PFS Marker Vc + R vs. R N Logrank % N in Marker A Subtype median days Vc + R vs. R P-value ITT CD68 OVERALL  0-25 11.5 mo vs 10.6 mo 40 vs 44 0.422 12.4 POSITIVE 0.9 mo PFS improvement CD68 OVERALL 26-50 12.1 mo vs 9.3 mo 114 vs 108 0.0588 32.9 POSITIVE 2.8 mo PFS improvement CD68 POSITIVE  0-25 14.1 mo vs 9.3 mo 50 vs 60 0.0934 16.3 FOLLICULAR 4.8 mo PFS improvement CD68 POSITIVE 26-50 13.4 mo vs 9.1 mo 84 vs 91 0.0289 25.9 FOLLICULAR 4.3 mo PFS improvement P65 INTENSITY <=1+ 11.6 mo vs 9.3 mo 41 vs 43 0.2455 12.4 CYTOPLASMIC 2.3 mo PFS improvement SIGNAL PSMB1/P11A C/G 14 mo vs 9.3 mo 115 vs 127 0.0218 35.9 4.7 mo improvement PSMB5/R24C C/T 17.6 mo vs 9.3 mo 41 vs 41 0.4016 12.1 8.3 mo improvement

EXAMPLE 3

Predictor pairs which correlated with a positive response are shown in Tables 6 and 7.

TABLE 6 Significant marker pairs. PFS Vc − R vs. R N Logrank Marker A Marker B median month Vc − R vs. R P-value FDR PSMB5/R24C P65 INTENSITY 27 mo vs. 10.4 mo 5 vs. 7 0.0439 0.489 C/T CYTOPLASMIC SIG- 16.6 mo improvement NAL <=1+ PSMB1/P11A 20S % POSITIVE 18.9 mo vs. 9.5 mo 50 vs 50 0.0145 0.447 C/G CYTOPLASMIC SIG- 9.4 improvement NAL: >90 PSMB1/P11A CD68 POSITIVE 16.6 mo vs. 9.1 mo 57 vs 61 0.0001 0.051 C/G FOLLICULAR: 0-50 7.5 mo improvement PSMB1/P11A CD68 POSITIVE 16.6 mo vs. 9.2 mo 24 vs 28 0.0365 0.471 C/G PERIFOLLICULAR: >50 7.4 improvement PSMB9/R60H P65 % NUCLEAR 16.2 mo vs. 9.5 mo 35 vs 28 0.0303 0.455 G/G STAINING: >0 6.7 improvement PSMB5/R24C CD68 POSITIVE 13.7 mo vs. 7.2 mo 18 vs 21 0.0220 0.447 C/T FOLLICULAR: 0-50 6.5 mo improvement HI Tumor BD CD68 OVERALL 22.8 mo vs. 16 mo 64 vs 68 0.0177 0.447 NO POSITIVE: 0-50 6.8 mo improvement HI Tumor BD CD68 POSITIVE 20.5 mo vs. 13.8 mo 64 vs 66 0.0310 0.455 NO FOLLICULAR: 0-50 6.7 mo improvement Prior RX: 1 CD68 POSITIVE 18.2 mo vs. 9.3 mo 63 vs 69 0.0129 0.447 FOLLICULAR: 0-50 8.9 mo improvement PSMB1/P11A Time since last 18.2 mo vs. 10.7 mo 72 vs 74 0.0198 0.447 C/G Rx: >1 year 7.5 mo improvement Prior Ritutux CD68 POSITIVE 15.9 mo vs. 9.2 mo 73 vs 86 0.0066 0.437 NO FOLLICULAR: 0-50 6.7 mo improvement PSMB1/P11A Age group: <=65 15.3 mo vs. 9.2 mo 86 vs 96 0.0071 0.437 C/G 6.1 mo improvement Sex 20S % NUCLEAR 13.7 mo vs. 7.7 mo 63 vs 48 0.0050 0.437 MALE STAINING: >20 6 mo improvement Race Group 20S % NUCLEAR 11.4 mo vs. 3.8 mo 11 vs 7 0.0320 0.455 OTHER STAINING: >20 7.6 mo improvement PSMB1/P11A PSMB5/R24C 13.7 mo vs. 7.8 mo 7 vs. 7 0.0221 0.4468 C/G C/T 5.9 mo improvement

TABLE 7 Significant marker pairs PFS Vc − R vs. R Logrank Combination median month P-value P65 Cytoplasmic signal >90% & 23.6 vs. 10.6 mo (13 mo) 0.0132 1 prior treatment* 16 vs. 8.9 mo (7.1 mo) n.s. CD68 Pos Follic (0-50) & 14.2 vs 8.5 mo (5.7 mo) 0.0025 P11A[C/G]** 14.4 vs 9.2 mo (5.2 mo) n.s.

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EXAMPLE 4

Appendix 2 presents an overall summary of the single-marker associations with clinical endpoint other than PFS and stratified by clinical covariates from the previous examples.

Appendix 3 outlines the data for all significant pair-wise combinations from the previous examples. Note: Selected=Biomarker positive, Not Selected=Biomarker negative.

EXAMPLE 5

The VISTA study was an open-label, randomized study of VELCADE/Melphalan/Prednisone versus Melphalan/Prednisone in subjects with previously untreated multiple myeloma. San Miguel, N. Engl. J. Med. 2008 Aug. 28; 359(9):906-17. The primary efficacy objective of this study was to determine whether the addition of VELCADE (Bortezomib for Injection) to standard melphalan/prednisone (MP) therapy improves the time to disease progression (TTP) in subjects with previously untreated multiple myeloma.

The exploratory objectives in biomarker analysis from the VISTA study were to identify patient populations that are more or less likely to respond to VELCADE/Melphalan/Prednisone versus Melphalan/Prednisone alone by:

-   -   Confirming the finding (from lymphoma studies) of a single         marker association of PSMB1 P11A and PSMB5 R24C with PFS and OS.     -   Association with other clinical endpoints including: time to         progression (TTP), complete response (CR), Overall response         rate, time to response and duration of response.

Association of PSMB1 P11A and PSMB5 R24C individually or in combination with TTP, PFS, and OS were estimated using the log rank test between treatment groups for biomarker positive and negative populations. The overall biomarker population by treatment arm had similar associations made. Medians of TTP, PFS, and OS, difference in median TTP, PFS, and OS between treatment groups, log rank P-value, hazard ratio and its 95% confidence intervals and frequencies of events were reported. Kaplan-Meier plots were presented for each biomarker. When positive associations were found for TTP, OS or PFS, then the other clinical endpoints were tested with similar methods and output. For ORR, Fishers exact test was used. The number and percentage of subjects falling into each response category were descriptively tabulated.

Table 8 shows the progression free survival benefit of 5.3 months with VELCADE-MP vs. MP alone in patients with PSMB1 P11A (C/G) marker.

Biomarker Biomarker Positive Negative Total Statistic Vmp mp Vmp mp Vmp mp Event/ 39/82 61/89 47/87 68/94 86/169 129/183 Total (47.6) (68.5) (54.0) (72.3) (50.9) (70.5) (%) Median 20.3 mo 15 mo 17.7 mo 11.2 mo 19 mo 12.6 mo (95% CI) (556, (253, (459, (254, (533, (279, 873) 511) 610) 436) 662) 463) HR 0.44 0.62 0.54 (Vmp vs (0.29, (0.43, (0.41, mp) 0.67) 0.90) 0.71) HR p- <.0001 0.0117 <.0001 Value (Vmp vs mp) Table 9 shows the overall survival benefit of 6 months with VELCADE-MP vs. MP alone in patients with PSMB1 P11A (C/G) marker.

Biomarker Positive Biomarker Negative Total Statistic Vmp mp Vmp mp Vmp mp Event/Total 47/82 65/89 42/87 55/94 89/169 120/183 (%) (57.3) (73.0) (48.3) (58.5) (52.7) (65.6) Median 52 39 58 46 56 42 (95% CI) (1322, (893, (1318, (965, (1372, (1014, 1845) 1412) —) 1745) 1845) 1470) HR 0.63 0.81 0.72 Vmp vs (0.44, (0.54, (0.55, mp) 0.92) 1.22) 0.95) HR p- 0.0167 0.3153 0.0179 Value (Vmp vs mp)

APPENDIX 2, TABLE 2.1 Overall survival (OS) by Protein Expression and by Covariate, IRC Review (Significant [p ≦ 0.05], Frequency of ≧10% or Higher) Marker: HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) HR (log scale) Evt/N Median Evt/N Median N Total 20S % POSITIVE CYTOPLASMIC SIGNAL: 0-20 2 Prior Lines of Therapy 8.28 (0.85, 80.83)

 1/10 — 3/4   809 122 20S % POSITIVE CYTOPLASMIC SIGNAL: 95-100 2 Prior Lines of Therapy 0.42 (0.17, 1.00)

14/35 1205 9/40 — 122 CD68 OVERALL POSITIVE: 26-50 2 Prior Lines of Therapy 0.33 (0.12, 0.87)

13/26 1205 7/30 — 111 CD68 POSITIVE PERIFOLLICULAR: 26-50 2 Prior Lines of Therapy 0.30 (0.09, 1.04)

 7/16 1205 5/27 —  98 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% 2 Prior Lines of Therapy 0.42 (0.19, 0.97)

19/52 — 9/44 — 125 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ 2 Prior Lines of Therapy 0.35 (0.14, 0.88)

19/55 — 7/43 — 125 CD68 OVERALL POSITIVE: 26-50 No High Tumor Burden 0.21 (0.06, 0.72)

14/54 — 3/46 — 204 CD68 POSITIVE PERIFOLLICULAR: 26-50 No High Tumor Burden 0.11 (0.01, 0.82)

10/41 — 1/33 — 182 P27 % NUCLEI POSITIVE: 0-20 No High Tumor Burden 3.91 (0.98, 15.69)

 3/29 — 6/17 — 215 20S INTENSITY CYTOPLASMIC SIGNAL: ≦2+ Intermediate FLIPI Score 5.43 (1.17, 25.14)

 2/48 — 9/41 — 168 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ Intermediate FLIPI Score 6.84 (0.80, 58.74)

 1/17 — 5/13 — 170 CD68 POSITIVE FOLLICULAR: 0-25 No Prior Rituximab Therapy 0.21 (0.05, 0.97)

11/36 — 3/25 1343 210 CD68 POSITIVE FOLLICULAR: 0-25 ≦65 years old 0.29 (0.10, 0.83)

14/46 — 5/41 — 292 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ Male 0.30 (0.12, 0.77)

10/27 — 8/62 — 204 CD68 POSITIVE PERIFOLLICULAR: 26-50 Male 0.29 (0.10, 0.83)

11/30 — 5/39 — 169 P27 % NUCLEI POSITIVE: 60-70 Male 0.09 (0.01, 0.93)

 4/12 — 1/14 — 202 CD68 OVERALL POSITIVE: 51-75 Ann Arbor Stage III 6.24 (1.25, 31.02)

 2/21 — 6/13 1078 144 20S % POSITIVE CYTOPLASMIC SIGNAL: 0-20 Ann Arbor Stage IV 7.22 (0.80, 65.02)

 1/15 — 4/11 1103 236 20S % POSITIVE CYTOPLASMIC SIGNAL: 95-100 Ann Arbor Stage IV 0.50 (0.27, 0.91)

25/56 1205 19/75  1343 236

APPENDIX 2, TABLE 2.2 OS by Germline Genetic Variant nd by Covariate, IRC Review (Significant [p ≦ 0.05], Frequency of ≧10% or Higher) HR R R Vc − R Vc − R Marker: Subgroup Marker: Level Subgroup (95% CI) HR (log scale) Evt/N Median Evt/N Median N Total PSMB9/R60H: A/A 3 Prior Lines of Therapy 6.92 (0.79, 60.79)

1/6  — 5/7  846  85 PSMB5/R24C: C/T Intermediate FLIPI Score 0.10 (0.01, 0.97)

4/10 971 1/16 — 186 PSMB5/R24C: C/T Ann Arbor Stage IV 0.22 (0.07, 0.66)

9/15 717 5/28 — 270

APPENDIX 2, TABLE 2.3 OS by Somatic Mutation and by Covariate, IRC Review (Significant [p ≦ 0.05], Frequency of ≧10% or Higher) Marker: HR R R Vc − R Vc −R Subgroup Marker: Level Subgroup (95% CI) HR (log scale) Evt/N Median Evt/N Median N Total NOTCH/X28DEL: MND 2 Prior Lines of Therapy 0.44 (0.20, 0.97)

20/56 — 10/48 — 109 NOTCH/P2513L: MD No High Tumor Burden 0.14 (0.02, 1.15)

 7/26 —  1/21 — 163 BCL2/P59L: MD High Tumor Burden 0.17 (0.04, 0.65)

5/6 282  4/14 — 172 BCL2/P59L: MD High FLIPI Score 0.21 (0.05, 0.86)

6/6 282 4/7 843 125 BCL2/P59L: MD No Prior Rituximab Therapy 0.12 (0.03, 0.48)

5/5 174  4/13 — 178 BCL2/P59L: MD Rest of World 0.22 (0.06,0.84

4/5 174  5/12 — 152 NOTCH/P2513L: MD >65 years old 0.30 (0.09, 1.03)

 8/13 795  4/13 —  92 BCL2/P59L: MD Female 0.26 (0.07, 0.92)

6/8 536  4/14 — 180 BCL2/R106H: MD Male 0.25 (0.07, 0.84)

 8/10 318  4/12 — 169 NOTCH/Q2460X: MD Male 0.11 (0.02, 0.70)

3/3 595  5/12 — 142 NOTCH/X28DEL: MND Male 0.57 (0.32, 1.00)

26/75 — 22/97 — 180 BCL2/P59L: MD Ann Arbor Stage IV 0.12 (0.03, 0.50)

5/5 174  4/12 — 149

APPENDIX 2, TABLE 2.4 Time to Progression (TTP), by Protein Expression and by Covariate, IRC Review (Significant [p ≦ 0.05], Frequency of ≧10% or Higher) Marker: HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) HR (log scale) Evt/N Median Evt/N Median N Total CD68 POSITIVE FOLLICULAR: 26-50 No Subgroup 0.66 (0.45, 0.96)

65/91 277 48/84 414 387 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% No Subgroup 0.75 (0.59, 0.96)

139/204 334 116/186 414 470 CD68 POSITIVE FOLLICULAR: 26-50 1 Prior Line of Therapy 0.51 (0.27, 0.94)

26/39 349 18/40 881 176 CD68 POSITIVE PERIFOLLICULAR: >75 1 Prior Line of Therapy 0.24 (0.09, 0.65)

13/18 275  7/16 716 174 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% 1 Prior Line of Therapy 0.67 (0.45, 0.98)

56/89 349 48/88 506 203 20S % NUCLEAR STAINING: 30-50 2 Prior Lines of Therapy 0 41 (0.18, 0.95)

11/13 239 13/22 431 122 CD68 OVERALL POSITIVE: 0-25 2 Prior Lines of Therapy 0.22 (0.05, 0.90)

6/8 142 4/7 771 111 CD68 POSITIVE PERIFOLLICULAR: 0-25 2 Prior Lines of Therapy 0.13 (0.03, 0.64)

7/8  70 4/7 771 98 CD68 POSITIVE FOLLICULAR: 51-75 3 Prior Lines of Therapy 9.40 (1.13, 78.09)

1/4 — 8/8 276 60 P27 SIGNAL INTENSITY: ≧2+ 4 Prior Lines of Therapy 3.02 (1.09, 8.34)

 9/15 348  8/10 144 32 CD68 OVERALL POSITIVE: 26-50 No High Tumor Burden 0.50 (0.29, 0.86)

37/54 357 22/46 881 204 CD68 POSITIVE FOLLICULAR: 26-50 No High Tumor Burden 0.50 (0.27, 0.93)

29/44 351 17/39 881 182 CD68 OVERALL POSITIVE: 26-50 High FLIPI Score 0.58 (0.36, 0.94)

36/45 277 35/52 366 181 CD68 POSITIVE FOLLICULAR: 26-50 High FLIPI Score 0.57 (0.33, 0.97)

31/37 205 25/36 347 156 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% High FLIPI Score 0.65 (0.45, 0.94)

61/83 239 53/77 358 193 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ High FLIPI Score 0.67 (0.46, 0.98)

60/80 275 51/76 358 193 P27 % NUCLEI POSITIVE: 60-70 Intermediate FLIPI Score 3.34 (1.20, 9.30)

 6/13 513 10/11 215 165 P65 % POSITIVE CYTOPLASMIC SIGNAL: ≦90% Intermediate FLIPI Score 2.77 (1.00, 7.64)

 5/16 567 15/19 351 170 P65 % NUCLEAR STAINING: 0 No Prior Rituximab Therapy 0.69 (0.49, 0.97)

 77/102 322 55/92 426 255 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% No Prior Rituximab Therapy 0.68 (0.49, 0.95)

 80/112 345  61/105 463 255 CD68 OVERALL POSITIVE: 0-25 ≦1 year since last anti-lymphoma treatment 2.66 (1.02, 6.96)

11/18 424 11/13 202 173 CD68 POSITIVE FOLLICULAR: 0-25 >1 year since last anti-lymphoma treatment 0.49 (0.26, 0.91)

23/34 357 20/33 519 235 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% >1 year since last anti-lymphoma treatment 0.69 (0.49, 0.96)

 77/117 357  61/112 519 288 CD68 OVERALL POSITIVE: 26-50 Rest of World 0.63 (0.40, 1.00)

40/51 277 34/52 367 198 CD68 OVERALL POSITIVE: 26-50 ≦65 years old 0.65 (0.44, 0.95)

57/77 278 50/84 414 329 CD68 POSITIVE FOLLICULAR: 26-50 ≦65 years old 0.55 (0.36, 0.86)

52/67 270 34/62 406 292 CD68 POSITIVE PERIFOLLICULAR: >75 ≦65 years old 0.46 (0.22, 0.98)

17/23 275 12/23 506 289 P27 SIGNAL INTENSITY: ≧2+ ≦65 years old 0.73 (0.55, 0.97)

104/153 281  91/149 406 344 P65 % NUCLEAR STAINING: 0 ≦65 years old 0.72 (0.53, 0.98)

 97/138 287  71/118 414 349 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% ≦65 years old 0.66 (0.50, 0.89)

108/154 278  83/142 422 349 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ ≦65 years old 0.74 (0.55, 0.98)

105/152 287  85/139 406 349 20S % POSITIVE CYTOPLASMIC SIGNAL: 0-20 >65 years old 0.14 (0.02, 1.21)

5/6 278 4/7 738 118 CD68 POSITIVE FOLLICULAR: 51-75 Female 2.38 (1.11, 5.13)

14/26 708 13/14 324 217 20S % NUCLEAR STAINING: 60-70 Male 0.37 (0.17, 0.84)

13/16 212 15/20 358 204 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ Male 0.58 (0.34, 1.00)

20/27 280 39/62 422 204 CD68 POSITIVE PERIFOLLICULAR: 26-50 Male 0.48 (0.27, 0.86)

22/30 239 26/39 429 169 P27 SIGNAL INTENSITY: ≧2+ Male 0.70 (0.48, 1.00)

52/72 280  69/101 360 202 P65 % NUCLEAR STAINING: 0 Male 0.67 (0.46, 0.98)

56/74 280 56/84 358 207 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% Male 0.61 (0.42, 0.87)

54/72 271 65/97 414 207 CD68 POSITIVE PERIFOLLICULAR: 26-50 Other 0.14 (0.01, 1.31)

4/4 128 4/5 346 22 CD68 POSITIVE FOLLICULAR: 26-50 White 0.59 (0.39, 0.89)

53/77 334 39/73 463 335 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% White 0.72 (0.55, 0.94)

119/179 345  99/162 426 406 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ Ann Arbor Stage III 0.26 (0.08, 0.90)

 7/11 204  7/11 464 151 20S % POSITIVE CYTOPLASMIC SIGNAL: 95-100 Ann Arbor Stage IV 0.66 (0.43, 1.00)

43/56 278 47/75 414 236 CD68 OVERALL POSITIVE: 26-50 Ann Arbor Stage IV 0.65 (0.42, 0.99)

44/56 277 45/68 366 222 P27 % NUCLEI POSITIVE: 30-50 Ann Arbor Stage IV 0.43 (0.20, 0.92)

15/19 278 13/23 485 237 P27 SIGNAL INTENSITY: ≧2+ Ann Arbor Stage IV 0.70 (0.50, 0.99)

64/85 283  73/113 358 237 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% Ann Arbor Stage IV 0.65 (0.46, 0.91)

67/87 275  66/104 366 240

APPENDIX 2, TABLE 2.5 TTP by Germline Genetic Variant and by Covariate, IRC review (Significant [p ≦ 0.05], Frequency of ≧10% or Higher) Marker: HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) HR (log scale) Evt/N Median Evt/N Median N Total PSMB1/P11A: C/G No Subgroup 0.70 (0.51, 0.96)

 82/127 288  74/115 426 542 PSMB9/V32I: C/C No Subgroup 0.80 (0.65, 0.99)

177/266 345 157/254 417 542 PSMB5/R24C: C/T 2 Prior Lines of Therapy 0.32 (0.11, 0.95)

 8/10 280  6/12 534 142 PSMB1/A171S: G/G High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB1/I208N: T/T High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB1/P11A: C/G High Tumor Burden 0.66 (0.44, 0.99)

52/72 253 44/65 358 296 PSMB1/P193L: C/C High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB2/E49X: G/G High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB2/G187V: G/G High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB2/L159F: C/C High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB5/L206M: C/C High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB5/R24C: C/T High Tumor Burden 0.39 (0.19, 0.77)

17/21 275 18/24 352 296 PSMB6/A234D: C/C High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB8/G8R: G/G High Tumor Burden 0.73 (0.56, 0.96)

104/140 271 105/145 344 296 PSMB8/R141C: C/C High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB8/V182M: G/G High Tumor Burden 0.74 (0.57, 0.97)

110/147 273 107/149 344 296 PSMB9/G9E: G/G High Tumor Burden 0.74 (0.56, 0.96)

110/145 271 107/148 344 296 PSMB9/V32I: C/C High Tumor Burden 0.73 (0.56, 0.96)

108/142 273 101/142 331 296 PSMB1/A171S: G/G High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB1/I208N: T/T High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB1/P193L: C/C High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273 75/110 350 222 PSMB2/E49X: G/G High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB2/G187V: G/G High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB2/L159F: C/C High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB5/L206M: C/C High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB6/A234D: C/C High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB6/P107A: C/C High FLIPI Score 0.68 (0.49, 0.93)

 81/107 275  74/108 350 222 PSMB8/G8R: G/G High FLIPI Score 0.69 (0.50, 0.95)

 77/105 273  73/107 350 222 PSMB8/R141C: C/C High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB8/V182M: G/G High FLIPI Score 0.68 (0.49, 0.92)

 84/112 273  75/110 350 222 PSMB9/G9E: G/G High FLIPI Score 0.69 (0.50, 0.94)

 84/111 273  75/109 348 222 PSMB9/V32I: C/C High FLIPI Score 0.65 (0.47, 0.89)

 80/105 239  71/105 348 222 PSMB1/P11A: C/G No Prior Rituximab Therapy 0.64 (0.43, 0.98)

49/68 330 43/70 464 287 PSMB9/V32I: C/C No Prior Rituximab Therapy 0.73 (0.55, 0.99)

 98/138 351  79/136 483 287 PSMB1/A171S: G/G >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB1/I208N: T/T >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB1/P11A: C/G >1 year since last anti-lymphoma treatment 0.60 (0.39, 0.91)

47/74 338 42/72 576 331 PSMB1/P193L: C/C >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB2/E49X: G/G >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB2/G187V: G/G >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB2/L159F: C/C >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB5/L206M: C/C >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB6/A234D: C/C >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB6/P107A: C/C >1 year since last anti-lymphoma treatment 0.71 (0.53, 0.94)

103/159 381  90/162 519 331 PSMB8/G8R: G/G >1 year since last anti-lymphoma treatment 0.73 (0.55, 0.98)

 96/155 414  86/159 519 331 PSMB8/R141C: C/C >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB8/V182M: G/G >1 year since last anti-lymphoma treatment 0.71 (0.54, 0.94)

104/165 381  91/166 529 331 PSMB9/G9E: G/G >1 year since last anti-lymphoma treatment 0.70 (0.53, 0.93)

104/163 381  91/165 519 331 PSMB9/V32I: C/C >1 year since last anti-lymphoma treatment 0.69 (0.51, 0.92)

102/160 379  86/158 529 331 PSMB1/A171S: G/G ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB1/I208N: T/T ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB1/P11A: C/G ≦65 years old 0.58 (0.40, 0.85)

62/96 288 50/86 506 392 PSMB1/P193L: C/C ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB2/E49X: G/G ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB2/G187V: G/G ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB2/L159F: C/C ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB5/L206M: C/C ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB5/R24C: C/C ≦65 years old 0.71 (0.55, 0.93)

115/170 334 103/167 429 392 PSMB6/A234D: C/C ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB6/P107A: C/C ≦65 years old 0.71 (0.55, 0.92)

126/189 330 113/190 435 392 PSMB8/G8R: G/G ≦65 years old 0.72 (0.56, 0.93)

124/189 330 111/186 422 392 PSMB8/R141C: C/C ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB8/V182M: G/G ≦65 years old 0.71 (0.55, 0.91)

131/198 326 115/194 435 392 PSMB9/G9E: G/G ≦65 years old 0.70 (0.55, 0.90)

131/196 326 115/193 431 392 PSMB9/R60H: G/G ≦65 years old 0.69 (0.50, 0.96)

 79/119 330  68/113 487 392 PSMB9/V32I: C/C ≦65 years old 0.69 (0.53, 0.89)

129/192 326 108/186 435 392 PSMB9/R60H: A/G Male 0.54 (0.31, 0.94)

22/28 273 34/48 351 241 PSMB1/A171S: G/G Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB1/I208N: T/T Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB1/P11A: C/G Ann Arbor Stage IV 0.64 (0.42, 0.96)

46/59 235 48/68 351 270 PSMB1/P193L: C/C Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB2/E49X: G/G Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB2/G187V: G/G Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB2/L159F: C/C Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB5/L206M: C/C Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB6/A234D: C/C Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB6/P107A: C/C Ann Arbor Stage IV 0.74 (0.55, 0.99)

 92/124 279  92/140 358 270 PSMB8/G8R: G/G Ann Arbor Stage IV 0.73 (0.54, 0.98)

 88/120 279  88/138 352 270 PSMB8/R141C: C/C Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB8/V182M: G/G Ann Arbor Stage IV 0.72 (0.54, 0.95)

 95/127 278  93/143 360 270 PSMB9/G9E: G/G Ann Arbor Stage IV 0.71 (0.53, 0.94)

 95/126 278  93/142 358 270 PSMB9/V32I: C/C Ann Arbor Stage IV 0.69 (0.51, 0.93)

 93/123 277  89/138 363 270

APPENDIX 2, TABLE 2.6 TTP by somatic mutation and by covariate, IRC review (Significant [p ≦ 0.05], Frequency of ≧10% and Higher) Marker: Level Subgroup HR (95% CI) HR (log scale) R Evt/N R Median Vc − R Evt/N Vc − R Median Marker: Subgroup N Total BCL2/A43G: MND No Subgroup 0.73 (0.55, 0.95)

110/161 334  96/154 435 315 BCL2/C.-11C>T: MND No Subgroup 0.77 (0.60, 1.00)

130/192 334 113/179 422 390 BCL2/E29K: MND No Subgroup 0.71 (0.53, 0.95)

102/150 326  87/139 435 318 BCL2/P46S: MND No Subgroup 0.73 (0.55, 0.97)

100/147 287  92/147 429 310 BCL2/P59S: MND No Subgroup 0.73 (0.55, 0.97)

100/145 288  94/147 429 309 BCL2/Q52P: MND No Subgroup 0.73 (0.55, 0.96)

105/153 288  97/154 429 307 BCL2/R106H: MND No Subgroup 0.72 (0.55, 0.95)

112/162 338  94/151 422 372 NOTCH/X28DEL: MND No Subgroup 0.78 (0.61, 1.00)

133/194 334 120/189 414 400 NOTCH/X28INS: MND No Subgroup 0.75 (0.59, 0.96)

138/198 334 123/195 414 401 BCL2/A43G: MND 1 Prior Line of Therapy 0.62 (0.40, 0.97)

45/72 349 35/67 624 139 BCL2/P59L: MD 1 Prior Line of Therapy 0.14 (0.02, 0.83)

3/3 398  6/11 553 139 NOTCH/X28INS: MND 1 Prior Line of Therapy 0.65 (0.44, 0.97)

53/84 365 47/88 553 178 BCL2/P46L: MD 2 Prior Lines of Therapy 0.14 (0.02, 1.28)

5/5 226 2/4 —  83 BCL2/R106H: MND 6 or More Prior Lines of Therapy 0.11 (0.01, 1.04)

4/4  50 4/5 305  11 NOTCH/G_A1702P: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.19)

5/6  70 4/5 305  11 NOTCH/I1681N: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.19)

5/6  70 4/5 305  11 NOTCH/L1679P: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.19)

5/6  70 4/5 305  11 NOTCH/L1679Q: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.19)

5/6  70 4/5 305  11 NOTCH/P2515FS4: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.19)

5/6  70 4/5 305  11 NOTCH/X26DEL: MND 6 or More Prior Lines of Therapy 0.14 (0.01, 1.31)

4/5 130 4/5 305  10 NOTCH/X26INS: MND 6 or More Prior Lines of Therapy 0.14 (0.01, 1.31)

4/5 130 4/5 305  10 NOTCH/X28DEL: MND 6 or More Prior Lines of Therapy 0.13 (0.01, 1.25)

4/5  70 4/5 305  11 NOTCH/X28INS: MND 6 or More Prior Lines of Therapy 0.12 (0.01, 1.10)

5/6  70 4/5 305  11 NOTCH/X26DEL: MND No High Tumor Burden 0.65 (0.43, 1.00)

56/87 422 36/71 630 163 NOTCH/X28INS: MND No High Tumor Burden 0.62 (0.42, 0.93)

62/98 422 41/82 630 184 BCL2/A43G: MND High Tumor Burden 0.65 (0.46, 0.92)

63/83 241 64/90 352 173 BCL2/E29K: MND High Tumor Burden 0.63 (0.43, 0.90)

59/79 239 57/82 358 174 BCL2/P46L: MND High Tumor Burden 0.61 (0.42, 0.90)

50/67 241 59/83 352 173 BCL2/P46S: MND High Tumor Burden 0.61 (0.42, 0.88)

55/73 239 63/89 348 170 BCL2/P59L: MD High Tumor Burden 0.21 (0.05, 0.86)

4/6 137 11/14 506 172 BCL2/P59L: MND High Tumor Burden 0.64 (0.44, 0.94)

54/72 241 56/80 344 172 BCL2/P59S: MND High Tumor Burden 0.60 (0.42, 0.87)

56/73 241 62/87 358 170 BCL2/Q52P: MND High Tumor Burden 0.60 (0.42, 0.85)

58/76 239 65/92 352 168 BCL2/R106H: MND High Tumor Burden 0.66 (0.46, 0.93)

63/83 241 64/93 352 209 NOTCH/F1593S: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/G_A1702P: MND High Tumor Burden 0.68 (0.49, 0.95)

68/90 241 69/96 348 187 NOTCH/I1681N: MND High Tumor Burden 0.69 (0.49, 0.96)

68/90 241 70/97 348 187 NOTCH/L1575P: MND High Tumor Burden 0.69 (0.48, 0.99)

56/76 253 64/91 358 168 NOTCH/L1586P: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/L1586Q: MND High Tumor Burden 0.68 (0.48, 0.96)

58/78 241 67/94 352 172 NOTCH/L1594P: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/L1597H: MND High Tumor Burden 0.68 (0.48, 0.96)

58/78 241 67/94 352 172 NOTCH/L1597_S1598INSG: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/L1601P: MND High Tumor Burden 0.67 (0.47, 0.96)

57/77 253 63/90 358 168 NOTCH/L1679P: MND High Tumor Burden 0.69 (0.49, 0.96)

68/90 241 70/97 348 187 NOTCH/L1679Q: MND High Tumor Burden 0.69 (0.49, 0.96)

68/90 241 70/97 348 187 NOTCH/L2458V: MND High Tumor Burden 0.70 (0.49, 0.99)

61/83 253 68/95 352 178 NOTCH/P2513L: MND High Tumor Burden 0.66 (0.45, 0.96)

57/76 253 51/71 358 198 NOTCH/P2515FS4: MND High Tumor Burden 0.69 (0.49, 0.96)

68/90 241 70/98 352 189 NOTCH/Q2441X: MND High Tumor Burden 0.70 (0.49, 0.99)

61/83 253 68/95 352 178 NOTCH/Q2460X: MND High Tumor Burden 0.69 (0.48, 1.00)

57/79 270 60/87 360 181 NOTCH/R1599 > QS: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/R1599P: MND High Tumor Burden 0.68 (0.48, 0.96)

58/78 241 67/94 352 172 NOTCH/V1579DEL: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/V1579E: MND High Tumor Burden 0.68 (0.48, 0.96)

58/78 241 67/94 352 172 NOTCH/V1579G: MND High Tumor Burden 0.68 (0.48, 0.98)

57/77 253 64/91 358 168 NOTCH/X28INS: MND High Tumor Burden 0.73 (0.53, 0.99)

 76/100 253  82/113 324 217 BCL2/A43G: MND High FLIPI Score 0.63 (0.41, 0.95)

47/66 239 43/61 358 127 BCL2/E29K: MND High FLIPI Score 0.64 (0.41, 0.99)

43/62 239 39/55 366 128 BCL2/P46L: MND High FLIPI Score 0.60 (0.38, 0.95)

37/53 210 40/55 352 124 BCL2/P59L: MND High FLIPI Score 0.64 (0.41, 1.00)

40/57 239 39/55 358 125 BCL2/P59S: MND High FLIPI Score 0.63 (0.41, 0.97)

42/59 224 41/57 352 123 BCL2/Q52P: MND High FLIPI Score 0.62 (0.41, 0.95)

44/61 224 43/60 352 121 BCL2/R106H: MND High FLIPI Score 0.60 (0.39, 0.92)

50/68 239 38/57 366 151 NOTCH/G_A1702P: MND High FLIPI Score 0.67 (0.45, 0.99)

52/72 212 49/67 346 139 NOTCH/I1681N: MND High FLIPI Score 0.67 (0.45, 0.99)

52/72 212 49/67 346 139 NOTCH/L1679P: MND High FLIPI Score 0.67 (0.45, 0.99)

52/72 212 49/67 346 139 NOTCH/L1679Q: MND High FLIPI Score 0.67 (0.45, 0.99)

52/72 212 49/67 346 139 NOTCH/P2515FS4: MND High FLIPI Score 0.66 (0.45, 0.99)

52/72 239 47/67 358 141 NOTCH/X28DEL: MND High FLIPI Score 0.66 (0.45, 0.96)

60/81 239 50/73 352 159 NOTCH/X28INS: MND High FLIPI Score 0.61 (0.42, 0.89)

61/81 239 52/76 352 160 BCL2/R106H: MD Intermediate FLIPI Score 3.47 (1.07, 11.29)

 4/10 924 10/11 281 130 BCL2/P46S: MND Low FLIPI Score 0.51 (0.27, 1.00)

24/38 349 14/38 —  83 BCL2/Q52P: MND Low FLIPI Score 0.53 (0.28, 1.00)

26/41 349 15/40 508  81 NOTCH/G_A1702P: MND Low FLIPI Score 0.52 (0.28, 0.97)

28/43 381 15/41 —  84 NOTCH/I1681N: MND Low FLIPI Score 0.52 (0.28, 0.97)

28/43 381 15/41 —  84 NOTCH/L1679P: MND Low FLIPI Score 0.52 (0.28, 0.97)

28/43 381 15/41 —  84 NOTCH/L1679Q: MND Low FLIPI Score 0.52 (0.28, 0.97)

28/43 381 15/41 —  84 NOTCH/X28INS: MND Low FLIPI Score 0.56 (0.32, 1.00)

30/48 349 19/48 771  98 BCL2/A43G: MND No Prior Rituximab Therapy 0.69 (0.48, 0.99)

69/98 345 52/85 485 183 BCL2/E29K: MND No Prior Rituximab Therapy 0.65 (0.45, 0.96)

65/93 345 46/76 508 186 BCL2/P46S: MND No Prior Rituximab Therapy 0.66 (0.45, 0.97)

60/87 287 48/79 508 175 BCL2/Q52P: MND No Prior Rituximab Therapy 0.68 (0.47, 0.99)

63/91 287 51/83 485 174 BCL2/R106H: MND No Prior Rituximab Therapy 0.67 (0.46, 0.98)

66/95 351 46/79 483 213 NOTCH/X28INS: MND No Prior Rituximab Therapy 0.71 (0.51, 1.00)

 79/112 357  64/107 463 226 BCL2/P46L: MD >1 year since last anti-lymphoma treatment 0.20 (0.05, 0.72)

10/10 408  4/10 637 180 NOTCH/X28IN8: MND >1 year since last anti-lymphoma treatment 0.72 (0.51, 1.00)

 75/113 379  67/119 506 237 BCL2/E29K: MND Rest of World 0.65 (0.43, 0.98)

55/75 241 41/63 415 154 BCL2/R106H: MND Rest of World 0.66 (0.44, 0.97)

60/83 275 42/69 422 184 NOTCH/X28INS: MND Rest of World 0.68 (0.48, 0.96)

72/97 275 59/92 406 194 BCL2/A43G: MND ≦65 years old 0.63 (0.46, 0.87)

 89/124 277  67/115 483 239 BCL2/C.-11C > T: MND ≦65 years old 0.69 (0.52, 0.93)

102/147 278  81/135 429 296 BCL2/E29K: MND ≦65 years old 0.60 (0.43, 0.84)

 83/117 275  59/103 485 241 BCL2/P46L: MD ≦65 years old 0.40 (0.16, 0.99)

13/14 226  8/15 485 238 BCL2/P46L: MND ≦65 years old 0.66 (0.47, 0.93)

 74/105 277  62/104 429 238 BCL2/P46S: MND ≦65 years old 0.62 (0.45, 0.87)

 80/111 275  66/113 456 236 BCL2/P59L: MND ≦65 years old 0.64 (0.45, 0.89)

 80/112 277  59/103 431 237 BCL2/P59S: MND ≦65 years old 0.63 (0.45, 0.87)

 81/110 275  69/114 435 235 BCL2/Q52P: MND ≦65 years old 0.63 (0.46, 0.86)

 85/117 275  69/117 435 234 BCL2/R106H: MND ≦65 years old 0.60 (0.44, 0.83)

 89/124 275  64/112 483 281 NOTCH/F1593S: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/G_A1702P: MND ≦65 years old 0.66 (0.48, 0.89)

 96/133 277  72/121 429 255 NOTCH/I1681N: MND ≦65 years old 0.66 (0.49, 0.90)

 96/133 277  73/122 422 255 NOTCH/L1575P: MND ≦65 years old 0.70 (0.50, 0.96)

 83/116 277  66/110 429 227 NOTCH/L1586P: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/L1586Q: MND ≦65 years old 0.69 (0.50, 0.95)

 86/120 277  69/114 422 234 NOTCH/L1594P: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/L1597H: MND ≦65 years old 0.69 (0.50, 0.95)

 86/120 277  69/114 422 234 NOTCH/L1597_S1598INSG: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/L1601P: MND ≦65 years old 0.68 (0.49, 0.94)

 84/117 277  65/109 431 227 NOTCH/L1679P: MND ≦65 years old 0.66 (0.49, 0.90)

 96/133 277  73/122 422 255 NOTCH/L1679Q: MND ≦65 years old 0.66 (0.49, 0.90)

 96/133 277  73/122 422 255 NOTCH/L2458V: MND ≦65 years old 0.67 (0.49, 0.92)

 86/120 275  71/117 422 237 NOTCH/P2513L: MND ≦65 years old 0.59 (0.41, 0.84)

 77/107 275 51/90 429 269 NOTCH/P2515FS4: MND ≦65 years old 0.67 (0.49, 0.90)

 96/134 278  74/123 431 259 NOTCH/Q2441X: MND ≦65 years old 0.67 (0.49, 0.92)

 86/120 275  71/115 422 237 NOTCH/Q2460X: MND ≦65 years old 0.64 (0.45, 0.90)

 78/110 275  60/104 422 239 NOTCH/R1599 > QS: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/R1599P: MND ≦65 years old 0.69 (0.50, 0.95)

 86/120 277  69/114 422 234 NOTCH/V1579DEL: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/V1579E: MND ≦65 years old 0.69 (0.50, 0.95)

 86/120 277  69/114 422 234 NOTCH/V1579G: MND ≦65 years old 0.69 (0.50, 0.95)

 84/117 277  66/110 429 227 NOTCH/X26DEL: MND ≦65 years old 0.70 (0.52, 0.94)

 96/137 281  78/132 431 273 NOTCH/X26INS: MND ≦65 years old 0.68 (0.51, 0.92)

 97/138 281  78/133 435 273 NOTCH/X28DEL: MND ≦65 years old 0.66 (0.50, 0.89)

106/149 278  83/140 422 298 NOTCH/X28INS: MND ≦65 years old 0.64 (0.48, 0.85)

109/149 277  85/143 429 298 NOTCH/P2513L: MND >65 years old 1.96 (1.03, 3.75)

16/33 616 24/33 414  92 BCL2/P59L: MD Female 0.28 (0.08, 0.95)

6/8 398  9/14 512 180 BCL2/P59S: MND Female 0.66 (0.44, 0.97)

66/97 348 42/73 512 178 BCL2/Q52P: MND Female 0.68 (0.46, 1.00)

 67/100 348 43/76 553 176 BCL2/R106H: MND Female 0.65 (0.44, 0.98)

65/96 357 38/70 506 203 BCL2/A43G: MND Male 0.60 (0.40, 0.91)

43/59 273 51/76 414 135 BCL2/E29K: MND Male 0.60 (0.39, 0.93)

40/55 271 46/68 414 138 BCL2/P46S: MND Male 0.64 (0.42, 0.98)

37/52 241 52/75 360 133 BCL2/Q52P: MND Male 0.64 (0.42, 0.97)

38/53 271 54/78 360 131 NOTCH/G_A1702P: MND Male 0.66 (0.44, 0.98)

44/63 241 56/81 360 145 NOTCH/I1681N: MND Male 0.67 (0.45, 1.00)

44/63 241 57/82 360 145 NOTCH/L1679P: MND Male 0.67 (0.45, 1.00)

44/63 241 57/82 360 145 NOTCH/L1679Q: MND Male 0.67 (0.45, 1.00)

44/63 241 57/82 360 145 NOTCH/L2458V: MND Male 0.63 (0.42, 0.95)

42/59 241 56/80 360 139 NOTCH/P2513L: MND Male 0.58 (0.38, 0.91)

39/54 239 42/63 414 155 NOTCH/P2515FS4: MND Male 0.65 (0.43, 0.96)

44/62 273 57/84 406 148 NOTCH/Q2441X: MND Male 0.64 (0.42, 0.95)

42/59 241 56/79 360 139 NOTCH/Q2460X: MND Male 0.61 (0.40, 0.94)

41/57 241 47/70 414 142 NOTCH/X28DEL: MND Male 0.69 (0.48, 1.00)

54/75 275 65/97 352 180 NOTCH/X28INS: MND Male 0.68 (0.47, 0.97)

57/78 275  67/100 358 181 BCL2/A43G: MND White 0.72 (0.54, 0.97)

 93/140 345  84/139 483 279 BCL2/E29K: MND White 0.70 (0.51, 0.96)

 85/129 345  77/127 506 282 BCL2/P46L: MD White 0.38 (0.16, 0.88)

18/21 346  8/16 512 279 BCL2/P46S: MND White 0.69 (0.51, 0.94)

 87/130 334  79/131 463 275 BCL2/P59L: MND White 0.73 (0.53, 0.99)

 85/129 334  74/123 431 278 BCL2/P59S: MND White 0.69 (0.51, 0.94)

 87/128 334  80/130 463 274 BCL2/Q52P: MND White 0.69 (0.51, 0.93)

 91/135 334  83/137 463 272 NOTCH/P2515FS4: MND White 0.75 (0.57, 1.00)

102/154 348  91/148 431 304 NOTCH/X28INS: MND White 0.75 (0.57, 0.97)

119/174 345 107/171 422 352 NOTCH/P2513L: MD Ann Arbor Stage III 0.40 (0.17, 0.95)

13/15 345 12/14 414 116 BCL2/A43G: MND Ann Arbor Stage IV 0.61 (0.41, 0.89)

57/71 275 52/83 414 154 BCL2/C.-11C > T: MND Ann Arbor Stage IV 0.66 (0.47, 0.94)

66/84 277  64/100 358 193 BCL2/E29K: MND Ann Arbor Stage IV 0.58 (0.39, 0.87)

53/67 275 44/73 415 154 BCL2/P46L: MND Ann Arbor Stage IV 0.59 (0.38, 0.91)

40/52 253 47/74 360 148 BCL2/P46S: MND Ann Arbor Stage IV 0.62 (0.42, 0.93)

48/61 253 53/81 358 147 BCL2/P59L: MND Ann Arbor Stage IV 0.63 (0.42, 0.96)

46/59 273 45/73 352 149 BCL2/P59S: MND Ann Arbor Stage IV 0.64 (0.43, 0.97)

45/58 273 51/79 360 147 BCL2/Q52P: MND Ann Arbor Stage IV 0.60 (0.41, 0.90)

49/62 273 53/83 360 145 BCL2/R106H: MND Ann Arbor Stage IV 0.57 (0.39, 0.84)

57/72 274 51/83 414 186 NOTCH/F1593S: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/G_A1702P: MND Ann Arbor Stage IV 0.61 (0.42, 0.88)

59/75 273 57/87 360 163 NOTCH/I1681N: MND Ann Arbor Stage IV 0.62 (0.43, 0.89)

59/75 273 58/88 358 163 NOTCH/L1575P: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/L1586P: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/L1586Q: MND Ann Arbor Stage IV 0.64 (0.44, 0.94)

52/67 273 55/83 360 150 NOTCH/L1594P: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/L1597H: MND Ann Arbor Stage IV 0.64 (0.44, 0.94)

52/67 273 55/83 360 150 NOTCH/L1597_S1598INSG: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/L1601P: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/L1679P: MND Ann Arbor Stage IV 0.62 (0.43, 0.89)

59/75 273 58/88 358 163 NOTCH/L1679Q: MND Ann Arbor Stage IV 0.62 (0.43, 0.89)

59/75 273 58/88 358 163 NOTCH/L2458V: MND Ann Arbor Stage IV 0.61 (0.42, 0.90)

53/68 273 56/86 360 154 NOTCH/P2513L: MND Ann Arbor Stage IV 0.55 (0.36, 0.84)

48/61 273 41/69 414 176 NOTCH/P2515FS4: MND Ann Arbor Stage IV 0.61 (0.42, 0.88)

58/74 273 58/91 366 167 NOTCH/Q2441X: MND Ann Arbor Stage IV 0.61 (0.42, 0.90)

53/68 273 56/85 360 154 NOTCH/Q2460X: MND Ann Arbor Stage IV 0.57 (0.38, 0.86)

49/64 273 49/79 414 156 NOTCH/R1599 > QS: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/R1599P: MND Ann Arbor Stage IV 0.64 (0.44, 0.94)

52/67 273 55/83 360 150 NOTCH/V1579DEL: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/V1579E: MND Ann Arbor Stage IV 0.64 (0.44, 0.94)

52/67 273 55/83 360 150 NOTCH/V1579G: MND Ann Arbor Stage IV 0.64 (0.43, 0.95)

50/64 253 52/79 360 143 NOTCH/X26DEL: MND Ann Arbor Stage IV 0.65 (0.45, 0.92)

61/76 275  66/101 360 180 NOTCH/X26INS: MND Ann Arbor Stage IV 0.64 (0.45, 0.91)

62/79 275  66/101 360 180 NOTCH/X28DEL: MND Ann Arbor Stage IV 0.64 (0.46, 0.91)

67/85 275  65/103 358 195 NOTCH/X28INS: MND Ann Arbor Stage IV 0.60 (0.42, 0.84)

70/87 274  66/105 358 196

APPENDIX 2, TABLE 2.7 Duration of response by protein expression and by covariate, IRC review. * (All reported groups are significant (p ≦ 0.05) and with a frequency ≧10%) Marker: HR HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total CD68 OVERALL POSITIVE: 0-25 High FLIPI Score 3.66 (1.10, 12.16)

 7/11 423 7/8 202 91 P27 % NUCLEI POSITIVE: 60-70 High FLIPI Score 0.14 (0.03, 0.74)

7/9 337 3/6 1162 96 20S INTENSITY CYTOPLASMIC SIGNAL: ≦2+ Intermediate FLIPI Score 2.39 (1.08, 5.26)

 9/25 554 20/26 264 99 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ Intermediate FLIPI Score 0.38 (0.17, 0.84)

17/25 352 10/23 813 99 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ No Prior Rituximab Therapy 0.53 (0.29, 0.97)

22/32 427 20/43 638 155 20S % NUCLEAR STAINING: 30-50 Prior Rituximab Therapy 2.39 (0.97, 5.86)

 9/13 356 13/14 245 97 CD68 OVERALL POSITIVE: 0-25 ≦1 year since last anti- lymphoma treatment 9.97 (1.13, 88.13)

5/7 354 5/5 145 79 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ ≦65 years old 0.55 (0.31, 0.98)

28/39 417 20/44 654 177 CD68 POSITIVE FOLLICULAR: 0-25 Female 0.38 (0.15, 1.01)

12/20 354  8/15 648 131 CD68 OVERALL POSITIVE: 51-75 Male 0.27 (0.07, 1.03)

5/7 279  6/12 784 98 CD68 OVERALL POSITIVE: >75 Male 0.10 (0.01, 1.02)

3/3 284 2/7 — 98 CD68 POSITIVE PERIFOLLICULAR: >75 Male 0.11 (0.01, 1.11)

3/3 284 2/7 — 86 P27 % NUCLEI POSITIVE: 60-70 Male 0.29 (0.08, 1.08)

5/6 281 7/9 502 99 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ Ann Arbor Stage III 0.16 (0.02, 1.19)

2/4 173 5/8 474 87

APPENDIX 2, TABLE 2.8 Duration of Response by Germline Genetic Variant and by Covariate, IRC Review. (All Reported Groups are Significant (p ≦ 1.05) and at a Frequency ≧10%) Marker: HR HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total PSMB9/R60H: A/G Male 0.42 (0.19, 0.94)

10/11 211 19/28 351 120 PSMB5/R24C: C/C Ann Arbor Stage II 3.29 (1.07, 10.09)

 4/18 — 13/20 438  43

APPENDIX 2, TABLE 2.9 Duration of Response by Somatic Mutation and by Covariate, IRC Review. (All Reported Groups are Significant (P ≦ 0.05) and at a Frequency ≧10%) Marker: Marker: HR HR R R Vc − R Vc − R Subgroup Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total BCL2/ P59L: MD No Subgroup 0.15 (0.03, 0.71)

4/5 343  9/15 488 177 BCL2/ P59L: MD 1 Prior Line of Therapy 0.11 (0.01, 1.21)

2/2 345  5/10 488 82 BCL2/ P59L: MD Prior Rituximab Therapy 0.14 (0.01, 1.33)

3/3 330 4/5 372 68 BCL2/ P46L: MD >1 year since last anti- lymphoma treatment 0.26 (0.06, 1.09)

5/5 356 4/8 502 115 BCL2/ P59L: MD >1 year since last anti- lymphoma treatment 0.13 (0.02, 0.82)

3/4 330  6/10 502 116 BCL2/ E29K: MND ≦65 years old 0.61 (0.37, 1.00)

32/49 353 32/66 648 128 NOTCH/ X28INS: MND ≦65 years old 0.66 (0.43, 1.00)

44/64 369 45/84 490 152 NOTCH/ P2513L: MND >65 years old 2.28 (1.02, 5.09)

10/23 948 18/22 356 62 BCL2/ P59L: MD White 0.10 (0.02, 0.57)

4/5 343  8/14 488 163 BCL2/ A43G: MND Ann Arbor Stage IV 0.57 (0.33, 1.00)

23/28 353 29/50 488 78 BCL2/ E29K: MND Ann Arbor Stage IV 0.51 (0.28, 0.93)

21/26 344 23/43 490 78 BCL2/ R106H: MND Ann Arbor Stage IV 0.54 (0.30, 0.96)

21/26 352 27/48 423 90 NOTCH/ X28INS: MND Ann Arbor Stage IV 0.58 (0.35, 0.98)

26/31 353 35/58 423 91

APPENDIX 2, TABLE 2.10 Time to Next Anti-Lymphoma Therapy by Protein Expression and by Covariate, IRC Review. (All Reported Groups are Significant (p ≦ 0.05) and at a Frequency ≧10%) Marker: HR HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total CD68 OVERALL POSITIVE: 0-25 No Subgroup 0.41 (0.23, 0.73)

30/44 409 19/41 1047 442 CD68 POSITIVE FOLLICULAR: 0-25 No Subgroup 0.54 (0.33, 0.88)

40/60 462 29/51 834 387 CD68 POSITIVE PERIFOLLICULAR: 0-25 No Subgroup 0.48 (0.27, 0.87)

26/39 374 20/41 1103 384 P27 SIGNAL TENSITY: ≧2+ No Subgroup 0.77 (0.60, 0.99)

127/199 533 114/196 700 463 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% No Subgroup 0.75 (0.58, 0.96)

129/204 505 108/186 726 470 CD68 POSITIVE PERIFOLLICULAR: >75 1 Prior Line of Therapy 0.43 (0.19, 0.97)

15/18 437 10/16 744 174 P27 % NUCLEI POSITIVE: 0-20 1 Prior Line of Therapy 0.38 (0.15, 0.97)

19/26 434  6/16 1047 204 P65 % NUCLEAR STAINING: 0 1 Prior Line of Therapy 0.63 (0.41, 0.95)

54/79 546 39/73 841 203 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% 1 Prior Line of Therapy 0.61 (0.42, 0.90)

59/89 550 47/88 841 203 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ 1 Prior Line of Therapy 0.64 (0.43, 0.95)

54/85 568 47/91 841 203 CD68 OVERALL POSITIVE: 0-25 2 Prior Lines of Therapy 0.20 (0.04, 1.04)

6/8 204 2/7 1005 111 CD68 POSITIVE PERIFOLLICULAR: 0-25 2 Prior Lines of Therapy 0.09 (0.01, 0.81)

6/8 171 1/7 — 98 P65 % NUCLEAR STAINING: ≦5% 2 Prior Lines of Therapy 0.31 (0.10, 0.92)

7/9 225  7/12 705 125 P27 % NUCLEI POSITIVE: 60-70 3 Prior Lines of Therapy 8.15 (0.93, 71.30)

1/6 — 5/5 227 74 P27 SIGNAL INTENSITY: ≧2+ 5 Prior Lines of Therapy 0.20 (0.04, 1.02)

5/6 228 3/8 939 16 P65 % NUCLEAR STAINING: ≦5% 5 Prior Lines of Therapy 0.13 (0.01, 1.34)

3/3 235 2/4 1235 16 CD68 OVERALL POSITIVE: 0-25 No High Tumor Burden 0.23 (0.07, 0.79)

 8/14 552  5/19 1235 204 CD68 OVERALL POSITIVE: 51-75 No High Tumor Burden 2.27 (0.98, 5.28)

10/25 — 12/18 511 204 CD68 POSITIVE FOLLICULAR: 0-25 No High Tumor Burden 0.38 (0.17, 0.87)

14/22 573 12/25 939 182 CD68 POSITIVE PERIFOLLICULAR: 0-25 No High Tumor Burden 0.22 (0.06, 0.74)

 8/13 501  5/16 1235 182 P27 % NUCLEI POSITIVE: 0-20 High Tumor Burden 0.54 (0.30, 0.98)

23/27 220 23/31 503 248 P27 % NUCLEI POSITIVE: 30-50 High Tumor Burden 0.45 (0.22, 0.93)

17/22 421 13/25 599 248 P27 SIGNAL INTENSITY: ≦1+ High Tumor Burden 0.42 (0.19, 0.93)

16/18 220 11/17 975 248 CD68 OVERALL POSITIVE: 0-25 Intermediate FLIPI Score 0.27 (0.08, 0.96)

 7/11 485  5/15 1235 159 CD68 POSITIVE FOLLICULAR: 0-25 Intermediate FLIPI Score 0.44 (0.19, 1.01)

14/20 421 11/20 939 141 CD68 POSITIVE PERIFOLLICULAR: 0-25 Intermediate FLIPI Score 0.27 (0.08, 0.95)

 7/13 501  5/17 1235 139 CD68 OVERALL POSITIVE: 0-25 Low FLIPI Score 0.32 (0.10, 0.99)

 8/10 422  5/11 1075 102 CD68 OVERALL POSITIVE: 0-25 No Prior Rituximab Therapy 0.36 (0.14, 0.93)

12/19 533  7/21 1103 241 CD68 POSITIVE FOLLICULAR: 0-25 No Prior Rituximab Therapy 0.40 (0.19, 0.84)

23/36 485 10/25 1103 210 CD68 POSITIVE PERIFOLLICULAR: 0-25 No Prior Rituximab Therapy 0.33 (0.11, 0.95)

12/18 533  5/15 — 208 20S % NUCLEAR STAINING: 60-70 Prior Rituximab Therapy 0.39 (0.15, 1.00)

17/21 343  6/12 1075 212 CD68 OVERALL POSITIVE: 0-25 Prior Rituximab Therapy 0.41 (0.19, 0.89)

18/25 235 12/20 834 201 P27 SIGNAL INTENSITY: ≧2+ Prior Rituximab Therapy 0.64 (0.44, 0.94)

60/88 421 48/85 718 210 P65 % NUCLEAR STAINING: ≦5% Prior Rituximab Therapy 0.29 (0.14, 0.64)

16/21 232 13/27 975 215 CD68 OVERALL POSITIVE: 0-25 >1 year since last anti- lymphoma treatment 0.26 (0.11, 0.60)

17/26 409  9/28 1235 269 CD68 POSITIVE FOLLICULAR: 0-25 >1 year since last anti- lymphoma treatment 0.48 (0.25, 0.93)

22/34 550 16/33 1005 235 CD68 POSITIVE PERIFOLLICULAR: 0-25 >1 year since last anti- lymphoma treatment 0.40 (0.18, 0.88)

15/24 533 11/27 1235 234 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% >1 year since last anti- lymphoma treatment 0.68 (0.48, 0.98)

 69/117 593  54/112 983 288 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ European Union 0.58 (0.34, 0.97)

34/52 533 25/52 1075 214 CD68 OVERALL POSITIVE: 0-25 European Union 0.40 (0.18, 0.90)

14/22 374 11/25 1103 211 CD68 POSITIVE PERIFOLLICULAR: >75 European Union 0.35 (0.13, 0.96)

13/17 675  7/14 1185 185 P27 % NUCLEI POSITIVE: 80-100 European Union 0.59 (0.35, 1.00)

29/41 655 27/51 939 214 P27 SIGNAL INTENSITY: ≧2+ European Union 0.67 (0.46, 0.99)

57/89 649 49/91 939 214 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% European Union 0.67 (0.46, 0.99)

57/92 552 48/87 975 216 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ European Union 0.45 (0.19, 1.02)

13/18 409 11/21 1005 216 CD68 OVERALL POSITIVE: 0-25 ≦65 years old 0.38 (0.20, 0.73)

24/34 374 15/32 1005 329 CD68 POSITIVE FOLLICULAR: 0-25 ≦65 years old 0.45 (0.26, 0.77)

33/46 332 24/41 764 292 CD68 POSITIVE PERIFOLLICULAR: 0-25 ≦65 years old 0.48 (0.24, 0.98)

20/31 332 13/29 1075 289 CD68 POSITIVE PERIFOLLICULAR: >75 ≦65 years old 0.45 (0.22, 0.91)

19/23 437 13/23 726 289 P27 % NUCLEI POSITIVE: 0-20 ≦65 years old 0.52 (0.29, 0.96)

26/34 327 19/32 834 344 P27 SIGNAL INTENSITY: ≧2+ ≦65 years old 0.74 (0.56, 0.98)

103/153 484  90/149 672 344 P65 % NUCLEAR STAINING: ≦5% ≦65 years old 0.54 (0.29, 1.00)

19/29 374 22/43 975 349 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% ≦65 years old 0.71 (0.53, 0.94)

103/154 484  84/142 719 349 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ ≦65 years old 0.72 (0.54, 0.96)

101/152 484  82/139 718 349 20S % NUCLEAR STAINING: 0-20 Female 0.53 (0.30, 0.93)

35/61 568 19/49 — 259 CD68 OVERALL POSITIVE: 0-25 Female 0.27 (0.10, 0.76)

16/26 434  5/18 1103 242 CD68 POSITIVE FOLLICULAR: 0-25 Female 0.45 (0.21, 0.96)

23/37 462 10/22 1103 217 CD68 POSITIVE PERIFOLLICULAR: 0-25 Female 0.29 (0.11, 0.79)

19/28 374  5/17 1107 215 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ Female 0.68 (0.46, 1.00)

 74/129 537 41/87 1047 263 20S % NUCLEAR STAINING: 60-70 Male 0.42 (0.19, 0.93)

14/16 247 12/20 518 204 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ Male 0.58 (0.34, 1.00)

20/27 421 37/62 764 204 CD68 OVERALL POSITIVE: 0-25 Male 0.46 (0.22, 0.99)

14/18 251 14/23 975 200 CD68 OVERALL POSITIVE: >75 Male 0.23 (0.07, 0.79)

8/9 427  4/11 — 200 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% Male 0.68 (0.47, 0.98)

51/72 427 62/97 726 207 CD68 POSITIVE FOLLICULAR: 0-25 Asian 0.13 (0.01, 1.09)

5/6 220 2/6 — 30 CD68 POSITIVE PERIFOLLICULAR: 26-50 Other 0.14 (0.01, 1.31)

4/4 341 4/5 658 22 CD68 OVERALL POSITIVE: 0-25 White 0.38 (0.20, 0.72)

24/35 409 16/35 1075 385 CD68 POSITIVE FOLLICULAR: 0-25 White 0.57 (0.34, 0.98)

32/48 462 25/42 834 335 CD68 POSITIVE PERIFOLLICULAR: 0-25 White 0.43 (0.22, 0.82)

19/27 501 19/39 1103 332 P27 SIGNAL INTENSITY: ≧2+ White 0.75 (0.57, 0.98)

113/177 533  99/170 718 403 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% White 0.73 (0.56, 0.96)

113/179 505  95/162 744 406 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ White 0.75 (0.57, 0.99)

109/176 533  94/165 744 406 CD68 OVERALL POSITIVE: 0-25 Ann Arbor Stage III 0.35 (0.14, 0.92)

12/16 276  9/12 905 144 CD68 POSITIVE FOLLICULAR: 0-25 Ann Arbor Stage III 0.40 (0.19, 0.83)

19/24 332 13/18 764 135 P27 % NUCLEI POSITIVE: 0-20 Ann Arbor Stage III 0.42 (0.17, 1.00)

14/16 418 12/15 613 149 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ Ann Arbor Stage III 0.36 (0.13, 0.99)

10/11 261  7/11 834 151 CD68 OVERALL POSITIVE: 0-25 Ann Arbor Stage IV 0.37 (0.15, 0.92)

15/22 434  8/23 1047 222 CD68 POSITIVE PERIFOLLICULAR: 0-25 Ann Arbor Stage IV 0.37 (0.14, 0.96)

11/15 374  8/22 1107 183

APPENDIX 2, TABLE 2.11 Time to Next Anti-Lymphoma Therapy by Germline Genetic Variant and by Covariate, IRC Review. (All Reported Groups are Significant (p ≦ 0.05) and at a Frequency of ≧10%) Marker: HR HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total PSMB1/A171S: G/G No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB1/I208N: T/T No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB1/P11A: C/G No Subgroup 0.68 (0.48, 0.94)

 78/127 550  63/115 939 542 PSMB1/P11A: G/G No Subgroup 0.57 (0.34, 0.97)

30/37 436 26/43 613 542 PSMB1/P193L: C/C No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB2/E49X: G/G No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB2/G187V: G/G No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB2/L159F: C/C No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB5/L206M: C/C No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB5/R24C: C/C No Subgroup 0.78 (0.62, 0.99)

147/235 546 127/223 719 542 PSMB6/A234D: C/C No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB6/P107A: C/C No Subgroup 0.79 (0.63, 0.98)

167/265 550 150/261 717 542 PSMB8/G8R: G/G No Subgroup 0.77 (0.61, 0.96)

165/264 537 144/256 719 542 PSMB8/R141C: C/C No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB8/V182M: G/G No Subgroup 0.78 (0.63, 0.97)

173/276 546 152/266 719 542 PSMB9/G9E: G/G No Subgroup 0.78 (0.63, 0.97)

172/274 546 152/265 718 542 PSMB9/V32I: C/C No Subgroup 0.79 (0.63, 0.99)

167/266 546 146/254 717 542 PSMB1/A171S: G/G 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB1/I208N: T/T 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB1/P11A: C/G 1 Prior Line of Therapy 0.56 (0.34, 0.95)

32/51 621 27/55 1047 231 PSMBI/P11A: G/G 1 Prior Line of Therapy 0.35 (0.13, 0.93)

11/11 443  7/14 700 231 PSMB1/P193L: C/C 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB2/E49X: G/G 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB2/G187V: G/G 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB2/L159F: C/C 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB5/L206M: C/C 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB6/A234D: C/C 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB6/P107A: C/C 1 Prior Line of Therapy 0.70 (0.49, 0.99)

 70/108 673  60/116 841 231 PSMB8/G8R: G/G 1 Prior Line of Therapy 0.68 (0.47, 0.97)

 69/109 673  55/111 852 231 PSMB8/R141C: C/C 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB8/V182M: G/G 1 Prior Line of Therapy 0.70 (0.50, 0.98)

 72/113 673  61/118 841 231 PSMB9/G9E: G/G 1 Prior Line of Therapy 0.71 (0.50, 1.00)

 71/112 673  61/118 841 231 PSMB1/A171S: G/G 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB1/I208N: T/T 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB1/P193L: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB2/E49X: G/G 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB2/G187V: G/G 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB2/L159F: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB5/L206M: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB5/R24C: C/C 5 Prior Lines of Therapy 0.16 (0.03, 0.79)

6/7 235 4/9 1235 21 PSMB6/A234D: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB6/P107A: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB8/G8R: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.00)

7/9 235  6/11 939 21 PSMB8/R141C: C/C 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB8/V182M: G/G 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB9/G9E: G/G 5 Prior Lines of Therapy 0.29 (0.08, 0.99)

7/9 235  6/12 939 21 PSMB9/V32I: C/C 5 Prior Lines of Therapy 0.25 (0.07, 0.86)

7/8 228  5/11 1235 21 PSMB1/A171S: G/G High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB1/I208N: T/T High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB1/P11A: C/G High Tumor Burden 0.63 (0.41, 0.96)

49/72 358 38/65 675 296 PSMB1/P193L: C/C High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB2/E49X: G/G High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB2/G187V: G/G High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB2/L159F: C/C High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB5/L206M: C/C High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB5/R24C: C/T High Tumor Burden 0.46 (0.24, 0.89)

19/21 317 18/24 536 296 PSMB6/A234D: C/C High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB6/P107A: C/C High Tumor Burden 0.73 (0.55, 0.96)

104/140 380  97/146 518 296 PSMB8/G8R: G/G High Tumor Burden 0.69 (0.52, 0.91)

104/140 374  94/145 521 296 PSMB8/R141C: C/C High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB8/V182M: G/G High Tumor Burden 0.72 (0.55, 0.95)

108/147 396  98/149 521 296 PSMB9/G9E: G/G High Tumor Burden 0.72 (0.55, 0.95)

107/145 396  98/148 518 296 PSMB9/V32I: C/C High Tumor Burden 0.71 (0.54, 0.94)

106/142 396  94/142 521 296 PSMB1/A171S: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB1/I208N: T/T >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB1/P11A: G/G >1 year since last anti- lymphoma treatment 0.47 (0.23, 0.97)

17/20 429 13/25 872 331 PSMB1/P193L: C/C >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB2/E49X: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB2/G187V: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB2/L159F: C/C >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB5/L206M: C/C >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB5/R24C: C/C >1 year since last anti- lymphoma treatment 0.70 (0.51, 0.97)

 81/137 649  68/141 983 331 PSMB6/A234D: C/C >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB6/P107A: C/C >1 year since last anti- lymphoma treatment 0.70 (0.52, 0.94)

 95/159 702  79/162 969 331 PSMB8/G8R: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 91/155 702  74/159 1005 331 PSMB8/R141C: C/C >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB8/V182M: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 98/165 688  80/166 969 331 PSMB9/G9E: G/G >1 year since last anti- lymphoma treatment 0.69 (0.51, 0.93)

 97/163 688  80/165 969 331 PSMB9/V32I: C/C >1 year since last anti- lymphoma treatment 0.68 (0.50, 0.91)

 96/160 649  76/158 969 331 PSMB1/A171S: G/G European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB1/I208N: T/T European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB1/P11A: C/G European Union 0.56 (0.34, 0.92)

34/49 462 29/51 1005 241 PSMB1/P193L: C/C European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB2/E49X: G/G European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB2/G187V: G/G European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB2/L159F: C/C European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB5/L206M: C/C European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB6/A234D: C/C European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB8/G8R: G/G European Union 0.71 (0.50, 1.00)

 70/111 649  62/117 939 241 PSMB8/R141C: C/C European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB8/V182M: G/G European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB9/G9E: G/G European Union 0.71 (0.51, 0.99)

 75/119 675  66/122 939 241 PSMB1/A171S: G/G ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB1/I208N: T/T ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB1/P11A: C/G ≦65 years old 0.62 (0.42, 0.91)

63/96 546 47/86 764 392 PSMB1/P11A: G/G ≦65 years old 0.40 (0.21, 0.78)

21/25 409 16/30 834 392 PSMB1/P193L: C/C ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB2/E49X: G/G ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB2/G187V: G/G ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB2/L159F: C/C ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB5/L206M: C/C ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB5/R24C: C/C ≦65 years old 0.71 (0.54, 0.93)

113/170 489  97/167 719 392 PSMB6/A234D: C/C ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB6/P107A: C/C ≦65 years old 0.72 (0.56, 0.93)

125/189 504 110/190 718 392 PSMB8/G8R: G/G ≦65 years old 0.72 (0.55, 0.93)

123/189 504 106/186 719 392 PSMB8/R141C: C/C ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB8/V182M: G/G ≦65 years old 0.72 (0.56, 0.92)

130/198 489 112/194 719 392 PSMB9/G9E: G/G ≦65 years old 0.72 (0.56, 0.93)

129/196 489 112/193 719 392 PSMB9/V32I: C/C ≦65 years old 0.72 (0.56, 0.93)

127/192 489 107/186 718 392 PSMB1/P11A: C/G Female 0.58 (0.36, 0.93)

42/75 546 30/66 1103 301 PSMB8/G8R: G/G Female 0.72 (0.52, 0.98)

 94/160 649  65/131 939 301 PSMB1/P11A: G/G Male 0.50 (0.25, 1.01)

17/19 421 15/25 631 241 PSMB9/R60H: A/G Male 0.43 (0.24, 0.76)

22/28 380 30/48 764 241 PSMB1/P11A: C/G Other 0.07 (0.01, 0.81)

2/3 164 6/9 557 27 PSMB1/P11A: C/G White 0.68 (0.47, 0.97)

 67/111 581 54/97 975 473 PSMB1/P11A: G/G White 0.54 (0.31, 0.94)

27/32 421 25/39 599 473 PSMB1/A171S: G/G Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB1/I208N: T/T Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB1/P193L: C/C Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB2/E49X: G/G Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB2/G187V: G/G Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB2/L159F: C/C Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB5/L206M: C/C Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB5/R24C: C/T Ann Arbor Stage IV 0.45 (0.20, 1.01)

11/15 421 13/28 991 270 PSMB6/A234D: C/C Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB6/P107A: C/C Ann Arbor Stage IV 0.72 (0.53, 0.98)

 84/124 485  77/140 602 270 PSMB8/G8R: G/G Ann Arbor Stage IV 0.73 (0.53, 1.00)

 80/120 457  74/138 602 270 PSMB8/R141C: C/C Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB8/V182M: G/G Ann Arbor Stage IV 0.72 (0.53, 0.97)

 86/127 457  78/143 639 270 PSMB9/G9E: G/G Ann Arbor Stage IV 0.71 (0.52, 0.97)

 86/126 457  78/142 602 270 PSMB9/V32I: C/C Ann Arbor Stage IV 0.72 (0.53, 0.98)

 84/123 457  76/138 639 270

APPENDIX 2, TABLE 2.12 Time to Next Anti-Lymphoma Therapy by Somatic Mutation and by Covariate, IRC review. (All Reported Groups are Significant (p ≦ 0.05) and at a Frequency of ≧10%) Marker: HR HR R R Vc − R Vc − R Subgroup Marker: Level Subgroup (95% CI) (log scale) Evt/N Median Evt/N Median N Total BCL2/A43G: MND No Subgroup 0.66 (0.49, 0.88)

104/161 501  84/154 791 315 BCL2/ C.-11C > T: MND No Subgroup 0.71 (0.54, 0.92)

127/192 501 102/179 719 390 BCL2/E29K: MND No Subgroup 0.64 (0.47, 0.86)

 98/150 484  77/139 791 318 BCL2/P46L: MND No Subgroup 0.70 (0.51, 0.95)

 86/135 504  77/139 743 314 BCL2/P46S: MND No Subgroup 0.73 (0.54, 0.98)

 92/147 504  84/147 751 310 BCL2/P59S: MND No Subgroup 0.72 (0.53, 0.96)

 92/145 504  84/147 751 309 BCL2/Q52P: MND No Subgroup 0.71 (0.53, 0.95)

 97/153 501  88/154 751 307 BCL2/R106H: MND No Subgroup 0.66 (0.50, 0.88)

108/162 489  84/151 751 372 NOTCH/ G_A1702P: MND No Subgroup 0.73 (0.55, 0.96)

113/175 501  93/161 726 337 NOTCH/I1681N: MND No Subgroup 0.73 (0.56, 0.97)

113/175 501  94/162 719 337 NOTCH/L1679P: MND No Subgroup 0.73 (0.56, 0.97)

113/175 501  94/162 719 337 NOTCH/L1679Q: MND No Subgroup 0.73 (0.56, 0.97)

113/175 501  94/162 719 337 NOTCH/L2458V: MND No Subgroup 0.75 (0.56, 0.99)

104/162 501  92/157 719 319 NOTCH/P2513L: MND No Subgroup 0.69 (0.50, 0.95)

 90/140 501  67/123 791 361 NOTCH/P2515FS4: MND No Subgroup 0.70 (0.53, 0.92)

114/176 501  92/166 751 344 NOTCH/Q2441X: MND No Subgroup 0.75 (0.57, 1.00)

103/161 501  92/155 719 319 NOTCH/Q2460X: MND No Subgroup 0.72 (0.53, 0.96)

 98/151 489  82/143 726 324 NOTCH/X26DEL: MND No Subgroup 0.74 (0.57, 0.97)

112/175 505 102/178 744 361 NOTCH/X26INS: MND No Subgroup 0.74 (0.56, 0.96)

114/179 505 103/180 744 361 NOTCH/X28DEL: MND No Subgroup 0.72 (0.56, 0.93)

128/194 503 109/189 719 400 NOTCH/X28INS: MND No Subgroup 0.70 (0.55, 0.90)

132/198 501 112/195 719 401 BCL2/A43G: MND 1 Prior Line of Therapy 0.54 (0.34, 0.86)

46/72 550 30/67 991 139 BCL2/C.-11C > T: MND 1 Prior Line of Therapy 0.61 (0.40, 0.92)

57/86 568 38/78 988 170 BCL2/E29K: MND 1 Prior Line of Therapy 0.54 (0.34, 0.88)

41/64 546 29/62 991 139 BCL2/P46L: MND 1 Prior Line of Therapy 0.59 (0.37, 0.97)

37/58 589 30/63 991 140 BCL2/P46S: MND 1 Prior Line of Therapy 0.61 (0.38, 0.97)

40/64 550 33/68 991 138 BCL2/P59S: MND 1 Prior Line of Therapy 0.62 (0.39, 0.99)

41/66 573 32/66 988 138 BCL2/Q52P: MND 1 Prior Line of Therapy 0.62 (0.39, 0.97)

42/67 550 35/71 988 138 BCL2/R106H: MND 1 Prior Line of Therapy 0.58 (0.37, 0.90)

49/73 550 33/68 991 162 NOTCH/P2515FS4: MND 1 Prior Line of Therapy 0.62 (0.40, 0.97)

48/75 573 35/72 988 149 NOTCH/X28DEL: MND 1 Prior Line of Therapy 0.67 (0.45, 1.00)

56/85 568 44/84 756 177 NOTCH/X28INS: MND 1 Prior Line of Therapy 0.63 (0.42, 0.93)

56/84 568 45/88 841 178 BCL2/C.-11C > T: MND 5 Prior Lines of Therapy 0.17 (0.03, 1.05)

3/3 221 3/7 939 11 NOTCH/X28DEL: MND 5 Prior Lines of Therapy 0.20 (0.04, 1.12)

4/4 342 3/7 939 11 BCL2/A43G: MND No High Tumor Burden 0.61 (0.37, 0.98)

42/78 774 27/64 — 142 BCL2/R106H: MND No High Tumor Burden 0.60 (0.37, 0.98)

46/79 690 26/58 1185 163 NOTCH/P2513L: MD No High Tumor Burden 0.44 (0.19, 0.99)

17/26 593  9/21 — 163 NOTCH/X28INS: MND No High Tumor Burden 0.63 (0.41, 0.96)

55/98 734 37/82 1107 184 BCL2/A43G: MND High Tumor Burden 0.60 (0.42, 0.86)

62/83 380 57/90 534 173 BCL2/C.-11C > T: MND High Tumor Burden 0.65 (0.47, 0.90)

 76/101 380  69/107 484 217 BCL2/E29K: MND High Tumor Burden 0.56 (0.38, 0.81)

60/79 374 52/82 542 174 BCL2/P46L: MND High Tumor Burden 0.57 (0.38, 0.84)

51/67 374 51/83 534 173 BCL2/P46S: MND High Tumor Burden 0.63 (0.43, 0.92)

52/73 374 56/89 488 170 BCL2/P59L: MND High Tumor Burden 0.66 (0.44, 0.97)

52/72 396 50/80 455 172 BCL2/P59S: MND High Tumor Burden 0.62 (0.42, 0.90)

53/73 396 54/87 534 170 BCL2/Q52P: MND High Tumor Burden 0.62 (0.42, 0.89)

55/76 374 58/92 534 168 BCL2/R106H: MND High Tumor Burden 0.59 (0.41, 0.84)

62/83 380 58/93 542 209 NOTCH/F1593S: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/G_A1702P: MND High Tumor Burden 0.62 (0.44, 0.88)

67/90 374 62/96 534 187 NOTCH/I1681N: MND High Tumor Burden 0.63 (0.45, 0.89)

67/90 374 63/97 534 187 NOTCH/L1586P: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/L1586Q: MND High Tumor Burden 0.65 (0.45, 0.94)

56/78 396 60/94 534 172 NOTCH/L1594P: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/L1597H: MND High Tumor Burden 0.65 (0.45, 0.94)

56/78 396 60/94 534 172 NOTCH/ L1597_S1598INSG: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/L1601P: MND High Tumor Burden 0.68 (0.47, 0.98)

55/77 410 59/90 488 168 NOTCH/L1679P: MND High Tumor Burden 0.63 (0.45, 0.89)

67/90 374 63/97 534 187 NOTCH/L1679Q: MND High Tumor Burden 0.63 (0.45, 0.89)

67/90 374 63/97 534 187 NOTCH/L2458V: MND High Tumor Burden 0.64 (0.45, 0.91)

61/83 380 61/95 534 178 NOTCH/P2513L: MND High Tumor Burden 0.54 (0.36, 0.80)

58/76 380 43/71 542 198 NOTCH/P2515FS4: MND High Tumor Burden 0.61 (0.43, 0.87)

67/90 380 61/98 534 189 NOTCH/Q2441X: MND High Tumor Burden 0.64 (0.45, 0.91)

61/83 380 61/95 534 178 NOTCH/Q2460X: MND High Tumor Burden 0.61 (0.42, 0.88)

59/79 380 54/87 542 181 NOTCH/R1599 > QS: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/R1599P: MND High Tumor Burden 0.65 (0.45, 0.94)

56/78 396 60/94 534 172 NOTCH/V1579DEL: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/V1579E: MND High Tumor Burden 0.65 (0.45, 0.94)

56/78 396 60/94 534 172 NOTCH/V1579G: MND High Tumor Burden 0.69 (0.48, 1.00)

55/77 410 60/91 488 168 NOTCH/X26DEL: MND High Tumor Burden 0.67 (0.47, 0.94)

63/88 396  68/107 518 198 NOTCH/X26INS: MND High Tumor Burden 0.66 (0.47, 0.93)

64/89 396  68/107 518 198 NOTCH/X28DEL: MND High Tumor Burden 0.64 (0.46, 0.89)

74/99 374  72/111 488 216 NOTCH/X28INS: MND High Tumor Burden 0.64 (0.47, 0.88)

 77/100 343  75/113 474 217 BCL2/P59L: MD High FLIPI Score 0.18 (0.03, 1.06)

4/6 211 6/7 658 125 BCL2/A43G: MND Intermediate FLIPI Score 0.60 (0.36, 1.00)

34/53 504 26/52 939 105 BCL2/C.-11C > T: MND Intermediate FLIPI Score 0.59 (0.38, 0.93)

44/66 504 33/63 939 136 BCL2/P46S: MND Intermediate FLIPI Score 0.59 (0.35, 1.00)

31/50 505 26/52 988 105 BCL2/P59S: MND Intermediate FLIPI Score 0.60 (0.35, 1.00)

31/48 505 27/52 939 105 BCL2/Q52P: MND Intermediate FLIPI Score 0.60 (0.36, 0.99)

32/51 505 28/54 988 105 BCL2/R106H: MND Intermediate FLIPI Score 0.51 (0.31, 0.82)

40/55 501 28/54 988 130 NOTCH/X28DEL: MND Intermediate FLIPI Score 0.65 (0.42, 1.00)

44/65 505 38/70 756 143 BCL2/E29K: MND No Prior Rituximab Therapy 0.65 (0.43, 0.97)

57/93 534 41/76 883 186 BCL2/P59L: MD No Prior Rituximab Therapy 0.15 (0.03, 0.80)

3/5 211  7/13 947 178 BCL2/A43G: MND Prior Rituximab Therapy 0.59 (0.38, 0.92)

44/63 428 37/69 719 132 BCL2/C.-11C > T: MND Prior Rituximab Therapy 0.58 (0.39, 0.86)

57/78 396 43/77 718 165 BCL2/E29K: MND Prior Rituximab Therapy 0.59 (0.37, 0.92)

41/57 428 36/63 719 132 BCL2/P59S: MND Prior Rituximab Therapy 0.60 (0.38, 0.95)

39/56 450 37/69 719 133 BCL2/R106H: MND Prior Rituximab Therapy 0.54 (0.36, 0.83)

50/67 421 39/72 719 159 NOTCH/G_A1702P: MND Prior Rituximab Therapy 0.60 (0.40, 0.91)

51/72 434 41/74 719 147 NOTCH/I1681N: MND Prior Rituximab Therapy 0.61 (0.41, 0.93)

51/72 434 42/75 719 147 NOTCH/L1586Q: MND Prior Rituximab Therapy 0.63 (0.41, 0.97)

44/63 443 41/73 719 136 NOTCH/L1597H: MND Prior Rituximab Therapy 0.63 (0.41, 0.97)

44/63 443 41/73 719 136 NOTCH/L1679P: MND Prior Rituximab Therapy 0.61 (0.41, 0.93)

51/72 434 42/75 719 147 NOTCH/L1679Q: MND Prior Rituximab Therapy 0.61 (0.41, 0.93)

51/72 434 42/75 719 147 NOTCH/L2458V: MND Prior Rituximab Therapy 0.61 (0.40, 0.93)

47/66 443 42/75 719 141 NOTCH/P2513L: MND Prior Rituximab Therapy 0.57 (0.35, 0.95)

39/57 450 25/51 751 154 NOTCH/P2515FS4: MND Prior Rituximab Therapy 0.61 (0.41, 0.92)

51/72 434 42/77 719 149 NOTCH/Q2441X: MND Prior Rituximab Therapy 0.61 (0.40, 0.93)

47/66 443 42/73 719 141 NOTCH/Q2460X: MND Prior Rituximab Therapy 0.58 (0.37, 0.90)

45/62 434 36/66 719 143 NOTCH/R1599P: MND Prior Rituximab Therapy 0.63 (0.41, 0.97)

44/63 443 41/73 719 136 NOTCH/V1579E: MND Prior Rituximab Therapy 0.63 (0.41, 0.97)

44/63 443 41/73 719 136 NOTCH/X26DEL: MND Prior Rituximab Therapy 0.65 (0.44, 0.98)

50/70 434 46/82 718 158 NOTCH/X26INS: MND Prior Rituximab Therapy 0.64 (0.43, 0.94)

52/74 434 47/84 719 158 NOTCH/X28DEL: MND Prior Rituximab Therapy 0.61 (0.42, 0.89)

60/83 427 49/86 672 175 NOTCH/X28INS: MND Prior Rituximab Therapy 0.60 (0.41, 0.87)

62/86 427 50/88 672 175 BCL2/A43G: MND >1 year since last anti- lymphoma treatment 0.63 (0.43, 0.94)

57/91 589 44/94 878 185 BCL2/C.-11C > T: MND >1 year since last anti- lymphoma treatment 0.62 (0.44, 0.88)

 73/112 560  55/112 878 233 BCL2/E29K: MND >1 year since last anti- lymphoma treatment 0.59 (0.39, 0.90)

52/82 550 39/83 883 185 BCL2/R106H: MND >1 year since last anti- lymphoma treatment 0.57 (0.39, 0.83)

65/96 534 45/94 878 217 NOTCH/P2513L: MND >1 year since last anti- lymphoma treatment 0.60 (0.39, 0.92)

50/78 560 37/81 878 213 NOTCH/P2515FS4: MND >1 year since last anti- lymphoma treatment 0.65 (0.44, 0.94)

 64/102 593  48/102 878 205 NOTCH/Q2460X: MND >1 year since last anti- lymphoma treatment 0.66 (0.44, 0.99)

53/84 573 43/86 841 185 NOTCH/X26INS: MND >1 year since last anti- lymphoma treatment 0.69 (0.48, 1.00)

 62/102 643  54/110 883 212 NOTCH/X28DEL: MND >1 year since last anti- lymphoma treatment 0.70 (0.49, 0.99)

 70/112 589  58/116 872 236 NOTCH/X28INS: MND >1 year since last anti- lymphoma treatment 0.64 (0.45, 0.90)

 73/113 573  59/119 872 237 BCL2/A43G: MND European Union 0.53 (0.33, 0.84)

41/66 649 32/72 1103 138 BCL2/C.-11C > T: MND European Union 0.57 (0.38, 0.86)

53/79 505 41/83 983 169 BCL2/E29K: MND European Union 0.58 (0.36, 0.94)

37/61 533 32/67 1075 138 BCL2/P46L: MND European Union 0.58 (0.35, 0.96)

34/56 533 29/64 1185 139 BCL2/P46S: MND European Union 0.59 (0.37, 0.94)

37/61 504 33/68 1075 136 BCL2/P59S: MND European Union 0.60 (0.37, 0.96)

36/60 505 34/69 983 136 BCL2/Q52P: MND European Union 0.60 (0.38, 0.94)

38/63 504 36/73 983 136 BCL2/R106H: MND European Union 0.57 (0.36, 0.89)

44/65 533 35/70 1005 160 NOTCH/G_A1702P: MND European Union 0.61 (0.39, 0.95)

44/72 533 36/74 983 147 NOTCH/I1681N: MND European Union 0.63 (0.40, 0.97)

44/72 533 37/75 983 147 NOTCH/L1586Q: MND European Union 0.63 (0.40, 0.99)

40/66 505 36/72 983 138 NOTCH/L1597H: MND European Union 0.63 (0.40, 0.99)

40/66 505 36/72 983 138 NOTCH/L1679P: MND European Union 0.63 (0.40, 0.97)

44/72 533 37/75 983 147 NOTCH/L1679Q: MND European Union 0.63 (0.40, 0.97)

44/72 533 37/75 983 147 NOTCH/P2513L: MND European Union 0.47 (0.28, 0.80)

39/59 504 22/52 — 159 NOTCH/P2515FS4: MND European Union 0.58 (0.38, 0.90)

48/77 533 36/77 1075 155 NOTCH/R1599P: MND European Union 0.63 (0.40, 0.99)

40/66 505 36/72 983 138 NOTCH/V1579E: MND European Union 0.63 (0.40, 0.99)

40/66 505 36/72 983 138 NOTCH/X26DEL: MND European Union 0.64 (0.42, 0.99)

44/72 552 42/84 1005 159 NOTCH/X26INS: MND European Union 0.63 (0.42, 0.96)

46/74 552 42/84 1005 159 NOTCH/X28DEL: MND European Union 0.62 (0.41, 0.92)

53/82 533 45/87 983 177 NOTCH/X28INS: MND European Union 0.61 (0.41, 0.90)

56/85 533 46/89 983 177 BCL2/A43G: MND ≦65 years old 0.66 (0.48, 0.91)

 84/124 484  65/115 743 239 BCL2/C.-11C > T: MND ≦65 years old 0.70 (0.52, 0.94)

101/147 484  81/135 718 296 BCL2/E29K: MND ≦65 years old 0.60 (0.43, 0.85)

 81/117 450  58/103 751 241 BCL2/P46L: MND ≦65 years old 0.69 (0.48, 0.97)

 71/105 485  59/104 743 238 BCL2/P46S: MND ≦65 years old 0.71 (0.51, 0.99)

 73/111 489  66/113 726 236 BCL2/P59S: MND ≦65 years old 0.71 (0.51, 0.99)

 74/110 489  68/114 726 235 BCL2/Q52P: MND ≦65 years old 0.71 (0.51, 0.98)

 78/117 485  69/117 726 234 BCL2/R106H: MND ≦65 years old 0.61 (0.44, 0.84)

 86/124 450  61/112 751 281 NOTCH/G_A1702P: MND ≦65 years old 0.69 (0.51, 0.95)

 91/133 462  71/121 719 255 NOTCH/I1681N: MND ≦65 years old 0.70 (0.51, 0.96)

 91/133 462  72/122 719 255 NOTCH/L1679P: MND ≦65 years old 0.70 (0.51, 0.96)

 91/133 462  72/122 719 255 NOTCH/L1679Q: MND ≦65 years old 0.70 (0.51, 0.96)

 91/133 462  72/122 719 255 NOTCH/L2458V: MND ≦65 years old 0.71 (0.52, 0.98)

 82/120 462  70/117 719 237 NOTCH/P2513L: MND ≦65 years old 0.62 (0.43, 0.89)

 74/107 462 50/90 751 269 NOTCH/P2515FS4: MND ≦65 years old 0.67 (0.49, 0.92)

 92/134 484  70/123 726 259 NOTCH/Q2441X: MND ≦65 years old 0.72 (0.52, 0.99)

 82/120 462  70/115 719 237 NOTCH/Q2460X: MND ≦65 years old 0.68 (0.48, 0.95)

 77/110 449  61/104 719 239 NOTCH/X26DEL: MND ≦65 years old 0.70 (0.52, 0.95)

 92/137 489  76/132 726 273 NOTCH/X26INS: MND ≦65 years old 0.70 (0.52, 0.95)

 93/138 501  77/133 726 273 NOTCH/X28DEL: MND ≦65 years old 0.68 (0.51, 0.90)

104/149 462  83/140 719 298 NOTCH/X28INS: MND ≦65 years old 0.67 (0.50, 0.89)

106/149 462  85/143 718 298 BCL2/P46L: MND Female 0.61 (0.39, 0.96)

51/86 535 31/68 1185 180 BCL2/P59S: MND Female 0.65 (0.43, 1.00)

57/97 533 36/73 947 178 BCL2/R106H: MND Female 0.65 (0.42, 0.99)

58/96 534 35/70 883 203 BCL2/A43G: MND Male 0.55 (0.36, 0.82)

45/59 343 47/76 743 135 BCL2/C.-11C > T: MND Male 0.62 (0.43, 0.90)

57/77 380 58/93 651 182 BCL2/E29K: MND Male 0.51 (0.33, 0.77)

43/55 337 43/68 743 138 BCL2/P46L: MD Male 0.11 (0.02, 0.63)

4/4 382  6/10 878 134 BCL2/P46S: MND Male 0.64 (0.42, 0.99)

38/52 396 49/75 695 133 BCL2/Q52P: MND Male 0.62 (0.41, 0.95)

39/53 396 50/78 695 131 BCL2/R106H: MND Male 0.61 (0.41, 0.90)

50/66 396 49/81 695 169 NOTCH/G_A1702P: MND Male 0.60 (0.40, 0.89)

47/63 337 51/81 726 145 NOTCH/I1681N: MND Male 0.61 (0.41, 0.90)

47/63 337 52/82 695 145 NOTCH/L1586Q: MND Male 0.65 (0.43, 0.98)

41/56 396 51/79 695 135 NOTCH/L1597H: MND Male 0.65 (0.43, 0.98)

41/56 396 51/79 695 135 NOTCH/L1679P: MND Male 0.61 (0.41, 0.90)

47/63 337 52/82 695 145 NOTCH/L1679Q: MND Male 0.61 (0.41, 0.90)

47/63 337 52/82 695 145 NOTCH/L2458V: MND Male 0.60 (0.40, 0.91)

44/59 337 51/80 695 139 NOTCH/P2513L: MND Male 0.52 (0.33, 0.82)

41/54 343 37/63 791 155 NOTCH/P2515FS4: MND Male 0.57 (0.38, 0.85)

47/62 380 51/84 743 148 NOTCH/Q2441X: MND Male 0.61 (0.40, 0.91)

44/59 337 51/79 695 139 NOTCH/Q2460X: MD Male 0.14 (0.03, 0.71)

3/3 127  8/12 645 142 NOTCH/Q2460X: MND Male 0.60 (0.39, 0.93)

42/57 343 43/70 726 142 NOTCH/R1599P: MND Male 0.65 (0.43, 0.98)

41/56 396 51/79 695 135 NOTCH/V1579E: MND Male 0.65 (0.43, 0.98)

41/56 396 51/79 695 135 NOTCH/X26DEL: MND Male 0.58 (0.39, 0.85)

49/65 396 58/95 726 162 NOTCH/X26INS: MND Male 0.56 (0.38, 0.82)

50/66 396 58/95 743 162 NOTCH/X28DEL: MND Male 0.63 (0.44, 0.91)

56/75 396 61/97 695 180 NOTCH/X28INS: MND Male 0.62 (0.44, 0.89)

59/78 396  63/100 651 181 BCL2/A43G: MND White 0.67 (0.49, 0.91)

 89/140 504  76/139 834 279 BCL2/C.-11C > T: MND White 0.70 (0.53, 0.93)

110/168 504  90/158 726 342 BCL2/E29K: MND White 0.63 (0.46, 0.87)

 83/129 485  70/127 834 282 BCL2/P46L: MND White 0.68 (0.49, 0.95)

 74/117 505  68/125 791 279 BCL2/P46S: MND White 0.70 (0.51, 0.96)

 81/130 505  74/131 834 275 BCL2/P59L: MND White 0.72 (0.52, 0.99)

 80/129 533  69/123 791 278 BCL2/P59S: MND White 0.68 (0.50, 0.94)

 81/128 505  73/130 834 274 BCL2/Q52P: MND White 0.69 (0.50, 0.94)

 85/135 504  77/137 834 272 BCL2/R106H: MND White 0.68 (0.50, 0.92)

 93/140 501  77/135 743 327 NOTCH/G_A1702P: MND White 0.72 (0.54, 0.97)

 97/152 504  82/143 743 295 NOTCH/I1681N: MND White 0.72 (0.54, 0.97)

 97/152 504  82/143 743 295 NOTCH/L1679P: MND White 0.72 (0.54, 0.97)

 97/152 504  82/143 743 295 NOTCH/L1679Q: MND White 0.72 (0.54, 0.97)

 97/152 504  82/143 743 295 NOTCH/L2458V: MND White 0.73 (0.54, 0.99)

 89/140 504  81/139 743 279 NOTCH/P2513L: MND White 0.67 (0.48, 0.94)

 78/122 504  59/108 841 319 NOTCH/P2515FS4: MND White 0.68 (0.50, 0.91)

 99/154 505  81/148 834 304 NOTCH/Q2441X: MND White 0.74 (0.54, 1.00)

 88/139 501  81/137 726 279 NOTCH/Q2460X: MND White 0.70 (0.51, 0.96)

 85/131 501  73/127 743 284 NOTCH/X26DEL: MND White 0.73 (0.55, 0.97)

 99/155 505  91/158 751 321 NOTCH/X26INS: MND White 0.72 (0.54, 0.96)

101/159 533  92/160 751 321 NOTCH/X28DEL: MND White 0.73 (0.55, 0.95)

111/169 504  98/167 726 351 NOTCH/X28INS: MND White 0.70 (0.53, 0.92)

115/174 504  99/171 743 352 BCL2/A43G: MND Ann Arbor Stage IV 0.60 (0.40, 0.91)

48/71 450 42/83 658 154 BCL2/C.-11C > T: MND Ann Arbor Stage IV 0.64 (0.44, 0.93)

60/84 450  54/100 639 193 BCL2/E29K: MND Ann Arbor Stage IV 0.59 (0.38, 0.91)

46/67 450 37/73 651 154 BCL2/P46L: MND Ann Arbor Stage IV 0.62 (0.39, 0.99)

35/52 449 38/74 651 148 BCL2/P59L: MD Ann Arbor Stage IV 0.17 (0.03, 0.88)

3/5 182  8/12 725 149 BCL2/R106H: MND Ann Arbor Stage IV 0.59 (0.39, 0.89)

50/72 449 42/83 651 186 NOTCH/G_A1702P: MND Ann Arbor Stage IV 0.61 (0.41, 0.90)

52/75 428 47/87 649 163 NOTCH/I1681N: MND Ann Arbor Stage IV 0.62 (0.42, 0.92)

52/75 428 48/88 649 163 NOTCH/L1679P: MND Ann Arbor Stage IV 0.62 (0.42, 0.92)

52/75 428 48/88 649 163 NOTCH/L1679Q: MND Ann Arbor Stage IV 0.62 (0.42, 0.92)

52/75 428 48/88 649 163 NOTCH/L2458V: MND Ann Arbor Stage IV 0.63 (0.42, 0.95)

46/68 434 46/86 651 154 NOTCH/P2513L: MND Ann Arbor Stage IV 0.55 (0.35, 0.87)

42/61 449 34/69 791 176 NOTCH/P2515FS4: MND Ann Arbor Stage IV 0.59 (0.39, 0.87)

51/74 434 46/91 658 167 NOTCH/Q2441X: MND Ann Arbor Stage IV 0.63 (0.42, 0.95)

46/68 434 46/85 651 154 NOTCH/Q2460X: MND Ann Arbor Stage IV 0.61 (0.39, 0.93)

43/64 449 41/79 658 156 NOTCH/X26DEL: MND Ann Arbor Stage IV 0.63 (0.43, 0.93)

53/76 457  54/101 651 180 NOTCH/X26INS: MND Ann Arbor Stage IV 0.63 (0.43, 0.91)

54/79 450  54/101 651 180 NOTCH/X28DEL: MND Ann Arbor Stage IV 0.63 (0.44, 0.91)

61/85 449  56/103 644 195 NOTCH/X28INS: MND Ann Arbor Stage IV 0.60 (0.42, 0.86)

64/87 434  57/105 644 196

APPENDIX 2, TABLE 2.13 Treatment Free Interval by Protein Expression and by Covariate, IRC Review. (All Reported Groups are Significant ( p ≦ 0.05) and at a Frequency of ≧10%) Marker: Sub- group HR (95% R R Vc − R Vc − R N Marker: Level Subgroup CI) HR (log scale) Evt/N Median Evt/N Median Total CD68 OVERALL POSITIVE: 0-25 No Subgroup 0.42 (0.23, 0.75)

30/44 269 19/41  883 442 CD68 POSITIVE FOLLICULAR: 0-25 No Subgroup 0.56 (0.34, 0.90)

40/60 307 29/51  671 387 CD68 POSITIVE PERIFOLLICULAR: 0-25 No Subgroup 0.49 (0.27, 0.89)

26/39 234 20/41  924 384 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% No Subgroup 0.77 (0.60, 1.00)

129/204 363 108/186  581 470 CD68 POSITIVE PERIFOLLICULAR: >75 1 Prior Line of Therapy 0.45 (0.20, 1.01)

15/18 297 10/16  587 174 P27 % NUCLEI POSITIVE: 0-20 1 Prior Line of Therapy 0.40 (0.16, 1.01)

19/26 293  6/16  883 204 P65 % NUCLEAR STAINING: 0 1 Prior Line of Therapy 0.66 (0.43, 0.99)

54/79 406 39/73  673 203 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% 1 Prior Line of Therapy 0.63 (0.43, 0.93)

59/89 409 47/88  673 203 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ 1 Prior Line of Therapy 0.66 (0.45, 0.98)

54/85 427 47/91  673 203 CD68 OVERALL POSITIVE: 0-25 2 Prior Lines of Therapy 0.20 (0.04, 1.02)

6/8  80 2/7  844 111 CD68 POSITIVE PERIFOLLICULAR: 0-25 2 Prior Lines of Therapy 0.09 (0.01, 0.81)

6/8  64 1/7 — 98 P65 % NUCLEAR STAINING: ≦5% 2 Prior Lines of Therapy 0.32 (0.11, 0.96)

7/9  85  7/12  542 125 P27 % NUCLEI POSITIVE: 60-70 3 Prior Lines of Therapy 8.31 (0.95, 72.50)

1/6 — 5/5  65 74 P27 SIGNAL INTENSITY: ≧2+ 5 Prior Lines of Therapy 0.22 (0.04, 1.13)

5/6  88 3/8  778 16 P65 % NUCLEAR STAINING: ≦5% 5 Prior Lines of Therapy 0.13 (0.01, 1.34)

3/3  95 2/4 1058 16 CD68 OVERALL POSITIVE: 0-25 No High Tumor Burden 0.23 (0.07, 0.80)

 8/14 411  5/19 — 204 CD68 OVERALL POSITIVE: 51-75 No High Tumor Burden 2.33 (1.00, 5.41)

10/25 — 12/18  349 204 CD68 POSITIVE FOLLICULAR: 0-25 No High Tumor Burden 0.40 (0.18, 0.91)

14/22 432 12/15 1058 182 CD68 POSITIVE PERIFOLLICULAR: 0-25 No High Tumor Burden 0.23 (0.07, 0.78)

 8/13 361  5/16 1058 182 P27 % NUCLEI POSITIVE: 30-50 High Tumor Burden 0.49 (0.24, 1.01)

17/22 280 13/25  483 248 P27 SIGNAL INTENSITY: ≦1+ High Tumor Burden 0.45 (0.20, 1.00)

16/18 122 11/17  818 248 CD68 OVERALL POSITIVE: 0-25 Intermediate FLIPI Score 0.27 (0.08, 0.98)

 7/11 343  5/15 1058 159 CD68 POSITIVE PERIFOLLICULAR: 0-25 Intermediate FLIPI Score 0.27 (0.08, 0.95)

 7/13 361  5/17 1058 139 CD68 OVERALL POSITIVE: 0-25 Low FLIPI Score 0.32 (0.10, 1.01)

 8/10 281  5/11  907 102 CD68 OVERALL POSITIVE: 0-25 No Prior Rituximab Therapy 0.38 (0.15, 0.99)

12/19 393  7/21  942 241 CD68 POSITIVE FOLLICULAR: 0-25 No Prior Rituximab Therapy 0.41 (0.19, 0.87)

23/36 344 10/25  942 210 CD68 POSITIVE PERIFOLLICULAR: 0-25 No Prior Rituximab Therapy 0.33 (0.12, 0.97)

12/18 393  5/15 — 208 20S % NUCLEAR STAINING 60-70 Prior Rituximab Therapy 0.40 (0.16, 1.02)

17/21 190  6/12  907 212 CD68 OVERALL POSITIVE: 0-25 Prior Rituximab Therapy 0.42 (0.20, 0.90)

18/25 115 12/20  671 201 P27 SIGNAL INTENSITY: ≧2+ Prior Rituximab Therapy 0.67 (0.46, 0.98)

60/88 272 48/85  554 210 P65 % NUCLEAR STAINING: ≦5% Prior Rituximab Therapy 0.31 (0.14, 0.67)

16/21  93 13/27  818 215 CD68 OVERALL POSITIVE: 0-25 >1 year since last anti- lymphoma treatment 0.27 (0.12, 0.63)

17/26 269  9/28 1058 269 CD68 POSITIVE FOLLICULAR: 0-25 >1 year since last anti- lymphoma treatment 0.50 (0.26, 0.97)

22/34 409 16/33  907 235 CD68 POSITIVE PERIFOLLICULAR: 0-25 >1 year since last anti- lymphoma treatment 0.42 (0.19, 0.92)

15/24 393 11/27 1058 234 20S INTENSITY CYTOPLASMIC SIGNAL: ≧3+ European Union 0.59 (0.35, 0.99)

34/52 393 25/52  907 214 CD68 OVERALL POSITIVE: 0-25 European Union 0.41 (0.18, 0.92)

14/22 234 11/25  942 211 CD68 POSITIVE PERIFOLLICULAR: >75 European Union 0.37 (0.14, 1.00)

13/17 533  7/14 1023 185 CD68 OVERALL POSITIVE: 0-25 ≦65 years old 0.39 (0.20, 0.76)

24/34 234 15/32  844 329 CD68 POSITIVE FOLLICULAR: 0-25 ≦65 years old 0.46 (0.27, 0.78)

33/46 190 24/41  603 292 CD68 POSITIVE PERIFOLLICULAR: 0-25 ≦65 years old 0.50 (0.24, 1.01)

20/31 143 13/29  907 289 CD68 POSITIVE PERIFOLLICULAR: >75 ≦65 years old 0.46 (0.22, 0.94)

19/23 297 13/23  587 289 P27 % NUCLEI POSITIVE: 0-20 ≦65 years old 0.53 (0.29, 0.97)

26/34 187 19/32  671 344 P65 % NUCLEAR STAINING: ≦5% ≦65 years old 0.54 (0.29, 1.00)

19/29 234 22/43  818 349 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% ≦65 years old 0.73 (0.55, 0.97)

103/154 343  84/142  557 349 P65 INTENSITY CYTOPLASMIC SIGNAL: ≧2+ ≦65 years old 0.74 (0.55, 0.99)

101/152 343  82/139  554 349 20S % NUCLEAR STAINING 0-20 Female 0.55 (0.32, 0.97)

35/61 427 19/49 — 259 CD68 OVERALL POSITIVE: 0-25 Female 0.28 (0.10, 0.76)

16/26 293  5/18  942 242 CD68 POSITIVE FOLLICULAR: 0-25 Female 0.46 (0.22, 0.96)

23/37 307 10/22  942 217 CD68 POSITIVE PERIFOLLICULAR: 0-25 Female 0.28 (0.10, 0.77)

19/28 234  5/17  942 215 20S % NUCLEAR STAINING 60-70 Male 0.43 (0.20, 0.95)

14/16 110 12/20  390 204 CD68 OVERALL POSITIVE: >75 Male 0.25 (0.07, 0.87)

8/9 272  4/11 — 200 CD68 POSITIVE FOLLICULAR: 0-25 Asian 0.13 (0.02, 1.17)

5/6 148 2/6 — 30 CD68 POSITIVE PERIFOLLICULAR: 26-50 Other 0.14 (0.01, 1.31)

4/4 217 4/5  495 22 CD68 OVERALL POSITIVE: 0-25 White 0.38 (0.20, 0.73)

24/35 269 16/35 907 385 CD68 POSITIVE FOLLICULAR: 0-25 White 0.59 (0.35, 1.00)

32/48 307 25/42 671 335 CD68 POSITIVE PERIFOLLICULAR: 0-25 White 0.43 (0.23, 0.83)

19/27 361 19/39 924 332 P65 % POSITIVE CYTOPLASMIC SIGNAL: >90% White 0.76 (0.58, 1.00)

113/179 363  95/162 587 406 CD68 OVERALL POSITIVE: 0-25 Ann Arbor Stage III 0.36 (0.14, 0.92)

12/16 135  9/12 745 144 CD68 POSITIVE FOLLICULAR: 0-25 Ann Arbor Stage III 0.44 (0.21, 0.90)

19/24 190 13/18 603 135 P27 % NUCLEI POSITIVE: 0-20 Ann Arbor Stage III 0.42 (0.17, 1.00)

14/16 275 12/15 449 149 P65 INTENSITY CYTOPLASMIC SIGNAL: ≦1+ Ann Arbor Stage III 0.38 (0.14, 1.02)

10/11 119  7/11 671 151 CD68 OVERALL POSITIVE: 0-25 Ann Arbor Stage IV 0.39 (0.16, 0.97)

15/22 293  8/23 883 222 CD68 POSITIVE PERIFOLLICULAR: 0-25 Ann Arbor Stage IV 0.37 (0.14, 0.96)

11/15 234  8/22 924 183

APPENDIX 2, TABLE 2.14 Treatment Free Interval by Germline Genetic Variant and by Covariate, IRC Review. (All Reported Groups are Significant (p ≦ 0.05) and at a Frequency of ≧10%) Marker: Sub- group HR (95% R R Vc − R Vc − R N Marker: Level Subgroup CI) HR (log scale) Evt/N Median Evt/N Median Total PSMB1/A171S: G/G No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB1/I208N: T/T No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB1/P11A: C/G No Subgroup 0.69 (0.50, 0.97)

 78/127 409  63/115 778 542 PSMB1/P193L: C/C No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB2/E49X: G/G No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB2/G187V: G/G No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB2/L159F: C/C No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB5/L206M: C/C No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB6/A234D: C/C No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB8/G8R: G/G No Subgroup 0.79 (0.63, 0.99)

165/264 396 144/256 581 542 PSMB8/R141C: C/C No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB8/V182M: G/G No Subgroup 0.80 (0.65, 1.00)

173/276 406 152/266 581 542 PSMB1/P11A: C/G 1 Prior Line of Therapy 0.58 (0.35, 0.97)

32/51 480 27/55 883 231 PSMB1/P11A: G/G 1 Prior Line of Therapy 0.37 (0.14, 0.98)

11/11 302  7/14 522 231 PSMB8/G8R: G/G 1 Prior Line of Therapy 0.70 (0.49, 0.99)

 69/109 533  55/111 690 231 PSMB1/A171S: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB1/I208N: T/T 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB1/P193L: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB2/E49X: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB2/G187V: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB2/L159F: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB5/L206M: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB5/R24C: C/C 5 Prior Lines of Therapy 0.17 (0.03, 0.86)

6/7 95 4/9 1058 21 PSMB6/A234D: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB6/P107A: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB8/G8R: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/11 778 21 PSMB8/R141C: C/C 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB8/V182M: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB9/G9E: G/G 5 Prior Lines of Therapy 0.29 (0.08, 1.01)

7/9 95  6/12 778 21 PSMB9/V32I: C/C 5 Prior Lines of Therapy 0.25 (0.07, 0.87)

7/8 88  5/11 1058 21 PSMB1/A171S: G/G High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB1/I208N: T/T High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB1/P11A: C/G High Tumor Burden 0.65 (0.42, 1.00)

49/72 218 38/65 499 296 PSMB1/P193L: C/C High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB2/E49X: G/G High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB2/G187V: G/G High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB2/L159F: C/C High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB5/L206M: C/C High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB5/R24C: C/T High Tumor Burden 0.48 (0.25, 0.93)

19/21 148 18/24 391 296 PSMB6/A234D: C/C High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB6/P107A: C/C High Tumor Burden 0.76 (0.57, 1.00)

104/140 234  97/146 365 296 PSMB8/G8R: G/G High Tumor Burden 0.71 (0.54, 0.94)

104/140 218  94/145 390 296 PSMB8/R141C: C/C High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB8/V182M: G/G High Tumor Burden 0.75 (0.57, 0.99)

108/147 234  98/149 366 296 PSMB9/G9E: G/G High Tumor Burden 0.75 (0.57, 0.99)

107/147 234  98/148 365 296 PSMB9/V32I: C/C High Tumor Burden 0.74 (0.56, 0.98)

106/142 234  94/142 366 296 PSMB1/A171S: G/G >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB1/I208N: T/T >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB1/P193L: C/C >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB2/E49X: G/G >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB2/G187V: G/G >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB2/L159F: C/C >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB5/L206M: C/C >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB5/R24C: C/C >1 year since last anti- lymphoma treatment 0.72 (0.52, 1.00)

 81/137 507  68/141 843 331 PSMB6/A234D: C/C >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB6/P107A: C/C >1 year since last anti- lymphoma treatment 0.72 (0.53, 0.97)

 95/159 561  79/162 800 331 PSMB8/G8R: G/G >1 year since last anti- lymphoma treatment 0.71 (0.52, 0.96)

 91/155 562  74/159 843 331 PSMB8/R141C: C/C >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB8/V182M: G/G >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 98/165 547  80/166 800 331 PSMB9/G9E: G/G >1 year since last anti- lymphoma treatment 0.71 (0.53, 0.95)

 97/163 547  80/165 800 331 PSMB9/V32I: C/C >1 year since last anti- lymphoma treatment 0.70 (0.51, 0.94)

 96/160 507  76/158 800 331 PSMB1/P11A: C/G European Union 0.56 (0.34, 0.93)

34/49 309 29/51 844 241 PSMB1/A171S: G/G ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB1/I208N: T/T ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB1/P11A: C/G ≦65 years old 0.63 (0.43, 0.92)

63/96 406 47/86 603 392 PSMB1/P11A: G/G ≦65 years old 0.42 (0.22, 0.81)

21/25 269 16/30 671 392 PSMB1/P193L: C/C ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB2/E49X: G/G ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB2/G187V: G/G ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB2/L159F: C/C ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB5/L206M: C/C ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB5/R24C: C/C ≦65 years old 0.73 (0.56, 0.96)

113/170 344  97/167 581 392 PSMB6/A234D: C/C ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB6/P107A: C/C ≦65 years old 0.74 (0.57, 0.96)

125/189 363 110/190 554 392 PSMB8/G8R: G/G ≦65 years old 0.74 (0.57, 0.96)

123/189 344 106/186 581 392 PSMB8/R141C: C/C ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB8/V182M: G/G ≦65 years old 0.74 (0.57, 0.95)

130/198 344 112/194 557 392 PSMB9/G9E: G/G ≦65 years old 0.74 (0.57, 0.95)

129/196 344 112/193 557 392 PSMB9/V32I: C/C ≦65 years old 0.74 (0.57, 0.96)

127/192 344 107/186 554 392 PSMB1/P11A: C/G Female 0.59 (0.37, 0.95)

42/75 406 30/66 924 301 PSMB9/R60H: A/G Male 0.45 (0.25, 0.79)

22/28 234 30/48 603 241 PSMB1/P11A: C/G Other 0.09 (0.01, 1.06)

2/3 76 6/9 394 27 PSMB1/P11A: C/G White 0.69 (0.48, 0.99)

 67/111 432 54/97 818 473 PSMB1/P11A: G/G White 0.57 (0.33, 0.98)

27/32 272 25/39 449 473 PSMB1/P11A: C/G Ann Arbor Stage III 0.53 (0.28, 0.98)

29/44 206 16/28 818 172

APPENDIX 2, TABLE 2.15 Treatment-Free Interval by Somatic Mutation and by Covariate, IRC Review. (All Reported Groups are Significant (p ≦ 0.05) and at a Frequency of ≧10%) Marker: Sub- HR (95% R R Vc − R Vc − R group Marker: Level Subgroup CI) HR (log scale) Evt/N Median Evt/N Median N Total BCL2/A43G: MND No Subgroup 0.67 (0.50, 0.90)

104/161 344 84/154  649 315 BCL2/C.-11C > T: MND No Subgroup 0.72 (0.56, 0.94)

127/192 361 102/179  587 390 BCL2/E29K: MND No Subgroup 0.65 (0.48, 0.87)

 98/150 343  77/139  649 318 BCL2/P46L: MND No Subgroup 0.72 (0.53, 0.98)

 86/135 362  77/139  595 314 BCL2/P59S: MND No Subgroup 0.73 (0.54, 0.99)

 92/145 362  84/147  629 309 BCL2/Q52P: MND No Subgroup 0.73 (0.55, 0.97)

 97/153 361  88/154  629 307 BCL2/R106H: MND No Subgroup 0.68 (0.51, 0.90)

108/162 344  84/151  629 372 NOTCH/G_A1702P: MND No Subgroup 0.74 (0.57, 0.98)

113/175 361  93/161  589 337 NOTCH/I1681N: MND No Subgroup 0.75 (0.57, 0.99)

113/175 361  94/162  587 337 NOTCH/L1679P: MND No Subgroup 0.75 (0.57, 0.99)

113/175 361  94/162  587 337 NOTCH/L1679Q: MND No Subgroup 0.75 (0.57, 0.99)

113/175 361  94/162  587 337 NOTCH/P2513L: MND No Subgroup 0.71 (0.52, 0.97)

 90/140 360  67/123  649 361 NOTCH/P2515FS4: MND No Subgroup 0.71 (0.54, 0.94)

114/176 361  92/166  629 344 NOTCH/Q2460X: MND No Subgroup 0.74 (0.55, 0.99)

 98/151 344  82/143  589 324 NOTCH/X26DEL: MND No Subgroup 0.76 (0.58, 0.99)

112/175 363 102/178  595 361 NOTCH/X26INS: MND No Subgroup 0.75 (0.58, 0.99)

114/179 363 103/180  595 361 NOTCH/X28DEL: MND No Subgroup 0.74 (0.57, 0.96)

128/194 361 109/189  583 400 NOTCH/X28INS: MND No Subgroup 0.72 (0.56, 0.93)

132/198 361 112/195  583 401 BCL2/A43G: MND 1 Prior Line of Therapy 0.55 (0.35, 0.88)

46/72 409 30/67  907 139 BCL2/C.-11C > T: MND 1 Prior Line of Therapy 0.63 (0.42, 0.95)

57/86 427 38/78  827 170 BCL2/E29K: MND 1 Prior Line of Therapy 0.56 (0.34, 0.90)

41/64 406 29/62  828 139 BCL2/P46L: MND 1 Prior Line of Therapy 0.61 (0.38, 1.00)

37/58 449 30/63  828 140 BCL2/P46S: MND 1 Prior Line of Therapy 0.62 (0.39, 0.99)

40/64 409 33/68  828 138 BCL2/Q52P: MND 1 Prior Line of Therapy 0.63 (0.40, 0.99)

42/67 409 35/71  827 138 BCL2/R106H: MND 1 Prior Line of Therapy 0.59 (0.38, 0.92)

49/73 409 33/68  828 162 NOTCH/P2515FS4: MND 1 Prior Line of Therapy 0.64 (0.41, 0.99)

48/75 432 35/72  827 149 NOTCH/X28INS: MND 1 Prior Line of Therapy 0.65 (0.44, 0.96)

56/84 427 45/88  673 178 BCL2/A43G: MND No High Tumor Burden 0.61 (0.38, 1.00)

42/78 632 27/64 — 142 BCL2/R106H: MND No High Tumor Burden 0.61 (0.38, 0.99)

46/79 549 26/58 1023 163 NOTCH/P2513L: MD No High Tumor Burden 0.45 (0.20, 1.01)

17/26 452  9/21 — 163 NOTCH/X28INS: MND No High Tumor Burden 0.64 (0.42, 0.98)

55/98 592 37/82  924 184 BCL2/A43G: MND High Tumor Burden 0.62 (0.43, 0.89)

62/83 234 57/90  379 173 BCL2/C.-11C > T: MND High Tumor Burden 0.68 (0.49, 0.94)

 76/101 234  69/107  326 217 BCL2/E29K: MND High Tumor Burden 0.57 (0.40, 0.84)

60/79 234 52/82  392 174 BCL2/P46L: MND High Tumor Burden 0.59 (0.40, 0.87)

51/67 234 51/83  379 173 BCL2/P46S: MND High Tumor Burden 0.64 (0.44, 0.94)

52/73 234 56/89  337 170 BCL2/P59L: MND High Tumor Burden 0.67 (0.45, 0.99)

52/72 254 50/80  318 172 BCL2/P59S: MND High Tumor Burden 0.63 (0.43, 0.93)

53/73 254 54/87  379 170 BCL2/Q52P: MND High Tumor Burden 0.63 (0.44, 0.92)

55/76 234 58/92  379 168 BCL2/R106H: MND High Tumor Burden 0.61 (0.43, 0.88)

62/83 234 58/93  392 209 NOTCH/G_A1702P: MND High Tumor Burden 0.64 (0.45, 0.91)

67/90 234 62/96  379 187 NOTCH/I1681N: MND High Tumor Burden 0.65 (0.46, 0.92)

67/90 234 63/97  379 187 NOTCH/L1586Q: MND High Tumor Burden 0.67 (0.47, 0.97)

56/78 254 60/94  379 172 NOTCH/L1597H: MND High Tumor Burden 0.67 (0.47, 0.97)

56/78 254 60/94  379 172 NOTCH/L1679P: MND High Tumor Burden 0.65 (0.46, 0.92)

67/90 234 63/97  379 187 NOTCH/L1679Q: MND High Tumor Burden 0.65 (0.46, 0.92)

67/90 234 63/97  379 187 NOTCH/L2458V: MND High Tumor Burden 0.66 (0.46, 0.94)

61/83 234 61/95  379 178 NOTCH/P2513L: MND High Tumor Burden 0.56 (0.37, 0.83)

58/76 234 43/71  392 198 NOTCH/P2515FS4: MND High Tumor Burden 0.63 (0.45, 0.90)

67/90 234 61/98  379 189 NOTCH/Q2441X: MND High Tumor Burden 0.66 (0.46, 0.94)

61/83 234 61/95  379 178 NOTCH/Q2460X: MND High Tumor Burden 0.63 (0.43, 0.91)

59/79 234 54/87  392 181 NOTCH/R1599P: MND High Tumor Burden 0.67 (0.47, 0.97)

56/78 254 60/94  379 172 NOTCH/V1579E: MND High Tumor Burden 0.67 (0.47, 0.97)

56/78 254 60/94  379 172 NOTCH/X26DEL: MND High Tumor Burden 0.69 (0.49, 0.98

63/88 254 68/107  379 198 NOTCH/X26INS: MND High Tumor Burden 0.68 (0.49, 0.96)

64/89 254 68/107  379 198 NOTCH/X28DEL: MND High Tumor Burden 0.67 (0.48, 0.92)

74/99 234  72/111  326 216 NOTCH/X28INS: MND High Tumor Burden 0.67 (0.49, 0.92)

 77/100 190  75/113  318 217 BCL2/A43G: MND Intermediate FLIPI Score 0.60 (0.36, 1.00)

34/53 362 26/52  778 105 BCL2/C.-11C > T: MND Intermediate FLIPI Score 0.60 (0.38, 0.95)

44/66 362 33/63  778 136 BCL2/R106H: MND Intermediate FLIPI Score 0.52 (0.32, 0.84)

40/55 361 28/54  671 130 BCL2/E29K: MND No Prior Rituximab Therapy 0.66 (0.44, 0.98)

57/93 393 41/76  718 186 BCL2/P59L: MD No Prior Rituximab Therapy 0.17 (0.03, 0.91)

3/5 217  7/13  779 178 BCL2/A43G: MND Prior Rituximab Therapy 0.62 (0.40, 0.96)

44/63 287 37/69  589 132 BCL2/C.-11C > T: MND Prior Rituximab Therapy 0.60 (0.40, 0.89)

57/78 254 43/77  554 165 BCL2/E29K: MND Prior Rituximab Therapy 0.62 (0.39, 0.97)

41/57 287 36/63  581 132 BCL2/P59S: MND Prior Rituximab Therapy 0.63 (0.40, 0.98)

39/56 307 37/69  589 133 BCL2/R106H: MND Prior Rituximab Therapy 0.57 (0.38, 0.88)

50/67 272 39/72  581 159 NOTCH/G_A1702P: MND Prior Rituximab Therapy 0.62 (0.41, 0.94)

51/72 288 41/74  589 147 NOTCH/I1681N: MND Prior Rituximab Therapy 0.64 (0.42, 0.96)

51/72 288 42/75  581 147 NOTCH/L1679P: MND Prior Rituximab Therapy 0.64 (0.42, 0.96)

51/72 288 42/75  581 147 NOTCH/L1679Q: MND Prior Rituximab Therapy 0.64 (0.42, 0.96)

51/72 288 42/75  581 147 NOTCH/L2458V: MND Prior Rituximab Therapy 0.63 (0.41, 0.96)

47/66 302 42/75  581 141 NOTCH/P2513L: MND Prior Rituximab Therapy 0.59 (0.36, 0.98)

39/57 307 25/51  649 154 NOTCH/P2515FS4: MND Prior Rituximab Therapy 0.63 (0.42, 0.96)

51/72 288 42/77  581 149 NOTCH/Q2441X: MND Prior Rituximab Therapy 0.63 (0.42, 0.97)

47/66 302 42/73  581 141 NOTCH/Q2460X: MND Prior Rituximab Therapy 0.60 (0.39, 0.93)

45/62 288 36/66  589 143 NOTCH/X26INS: MND Prior Rituximab Therapy 0.66 (0.45, 0.98)

52/74 288 47/84  581 158 NOTCH/X28DEL: MND Prior Rituximab Therapy 0.64 (0.43, 0.93)

60/83 280 49/86  554 175 NOTCH/X28INS: MND Prior Rituximab Therapy 0.62 (0.43, 0.91)

62/86 280 50/88  554 175 BCL2/A43G: MND >1 year since last anti- lymphoma treatment 0.65 (0.44, 0.96)

57/91 449 44/94  716 185 BCL2/C.-11C > T: MND >1 year since last anti- lymphoma treatment 0.64 (0.45, 0.90)

 73/112 419  55/112  716 233 BCL2/E29K: MND >1 year since last anti- lymphoma treatment 0.60 (0.40, 0.91)

52/82 409 39/83  718 185 BCL2/R106H: MND >1 year since last anti- lymphoma treatment 0.58 (0.40, 0.85)

65/96 392 45/94  716 217 NOTCH/P2513L: MND >1 year since last anti- lymphoma treatment 0.61 (0.40, 0.94)

50/78 419 37/81  716 213 NOTCH/P2515FS4: MND >1 year since last anti- lymphoma treatment 0.66 (0.45, 0.96)

 64/102 452  48/102  716 205 NOTCH/X28INS: MND >1 year since last anti- lymphoma treatment 0.66 (0.47, 0.93)

 73/113 432  59/119  709 237 BCL2/A43G: MND European Union 0.54 (0.34, 0.86)

41/66 507 32/72  942 138 BCL2/C.-11C > T: MND European Union 0.58 (0.38, 0.87)

53/79 363 41/83  843 169 BCL2/E29K: MND European Union 0.60 (0.37, 0.96)

37/61 393 32/67  907 138 BCL2/P46L: MND European Union 0.59 (0.36, 0.97)

34/56 393 29/64 1023 139 BCL2/P46S: MND European Union 0.60 (0.37, 0.96)

37/61 362 33/68  907 136 BCL2/P59S: MND European Union 0.61 (0.38, 0.97)

36/60 363 34/69  843 136 BCL2/Q52P: MND European Union 0.61 (0.38, 0.96)

38/63 362 36/73  843 136 BCL2/R106H: MND European Union 0.58 (0.37, 0.90)

44/65 393 35/70  844 160 NOTCH/G_A1702P: MND European Union 0.62 (0.40, 0.96)

44/72 393 36/74  843 147 NOTCH/I1681N: MND European Union 0.64 (0.41, 0.99)

44/72 393 37/75  843 147 NOTCH/L1679P: MND European Union 0.64 (0.41, 0.99)

44/72 393 37/75  843 147 NOTCH/L1679Q: MND European Union 0.64 (0.41, 0.99)

44/72 393 37/75  843 147 NOTCH/P2513L: MND European Union 0.48 (0.28, 0.81)

39/59 362 22/52  942 159 NOTCH/P2515FS4: MND European Union 0.59 (0.38, 0.91)

48/77 393 36/77  907 155 NOTCH/X26INS: MND European Union 0.64 (0.42, 0.98)

46/74 411 42/84  844 159 NOTCH/X28DEL: MND European Union 0.63 (0.42, 0.94)

53/82 393 45/87  843 177 NOTCH/X28INS: MND European Union 0.62 (0.42, 0.91)

56/85 393 46/89  843 177 BCL2/A43G: MND ≦65 years old 0.67 (0.48, 0.93)

 84/124 343  65/115  595 239 BCL2/C.-11C > T: MND ≦65 years old 0.72 (0.54, 0.96)

101/147 341  81/135  554 296 BCLW/E29K: MND ≦65 years old 0.61 (0.44, 0.86)

 81/117 307  58/103  649 241 BCL2/P46L: MND ≦65 years old 0.70 (0.49, 0.99)

 71 /105 344  59/104  589 238 BCL2/Q52P: MND ≦65 years old 0.72 (0.52, 1.00)

 78/117 344  69/117  589 234 BCL2/R106H: MND ≦65 years old 0.62 (0.44, 0.86)

 86/124 309  61/112  649 281 NOTCH/G_A1702P: MND ≦65 years old 0.71 (0.52, 0.96)

 91/133 309  71/121  587 255 NOTCH/I1681N: MND ≦65 years old 0.72 (0.52, 0.98)

 91/133 309  72/122  581 255 NOTCH/L1679P: MND ≦65 years old 0.72 (0.52, 0.98)

 91/133 309  72/122  581 255 NOTCH/L1679Q: MND ≦65 years old 0.72 (0.52, 0.98)

 91/133 309  72/122  581 255 NOTCH/L2458V: MND ≦65 years old 0.73 (0.53, 1.00)

 82/120 309  70/117  581 237 NOTCH/P2513L: MND ≦65 years old 0.63 (0.44, 0.91)

 74/107 309 50/90  649 269 NOTCH/P2515FS4: MND ≦65 years old 0.68 (0.50, 0.93)

 92/134 341  70/123  589 259 NOTCH/Q2460X: MND ≦65 years old 0.69 (0.49, 0.96)

 77/110 307  61/104  581 239 NOTCH/X26DEL: MND ≦65 years old 0.71 (0.53, 0.97)

 92/137 344  76/132  595 273 NOTCH/X26INS: MND ≦65 years old 0.72 (0.53, 0.97)

 93/138 344  77/133  589 273 NOTCH/X28DEL: MND ≦65 years old 0.69 0.52, 0.93)

104/149 309  83/140  581 298 NOTCH/X28INS: MND ≦65 years old 0.68 (0.51, 0.91)

106/149 309  85/143  554 298 BCL2/P46L: MND Female 0.62 (0.40, 0.98)

51/86 393 31/68 1023 180 BCL2/A43G: MND Male 0.56 (0.37, 0.84)

45/59 215 47/76  587 135 BCL2/C.-11C > T: MND Male 0.63 (0.44, 0.92)

57/77 234 58/93  534 182 BCL2/E29K: MND Male 0.52 (0.34, 0.79)

43/55 190 43/68  587 138 BCL2/P46L: MD Male 0.11 (0.02, 0.63)

4/4 244 6/10  716 134 BCL2/Q52P: MND Male 0.64 (0.42, 0.98)

39/53 254 50/78  543 131 BCL2/R106H: MND Male 0.62 (0.42, 0.93)

50/66 254 49/81  543 169 NOTCH/G_A1702P: MND Male 0.61 (0.41, 0.91)

47/63 190 51/81  581 145 NOTCH/I1681N: MND Male 0.62 (0.42, 0.92)

47/63 190 52/82  543 145 NOTCH/L1679P: MND Male 0.62 (0.42, 0.92)

47/63 190 52/82  543 145 NOTCH/L1679Q: MND Male 0.62 (0.42, 0.92)

47/63 190 52/82  543 145 NOTCH/L2458V: MND Male 0.62 (0.41, 0.93)

44/59 190 51/80  543 139 NOTCH/P2513L: MND Male 0.54 (0.35, 0.85)

41/54 190 37/63  629 155 NOTCH/P2515FS4: MND Male 0.58 (0.39, 0.87)

47/62 234 51/84  587 148 NOTCH/Q2441X: MND Male 0.62 (0.41, 0.93)

44/59 190 51/79  543 139 NOTCH/Q2460X: MD Male 0.14 (0.03, 0.71)

3/3 55  8/12  504 142 NOTCH/Q2460X: MND Male 0.62 (0.40, 0.95)

42/57 190 43/70  581 142 NOTCH/X26DEL: MND Male 0.59 (0.40, 0.87)

49/65 254 58/95  583 162 NOTCH/X26INS: MND Male 0.57 (0.39, 0.84)

50/66 234 58/95  583 162 NOTCH/X28DEL: MND Male 0.65 (0.45, 0.94)

56/75 254 61/97  543 180 NOTCH/X28INS: MND Male 0.64 (0.45, 0.91)

59/78 234  63/100  534 181 BCL2/A43G: MND White 0.68 (0.50, 0.93)

 89/140 361  76/139  671 279 BCL2/C.-11C > T: MND White 0.72 (0.54, 0.95)

110/168 362  90/158  589 342 BCL2/E29K: MND White 0.64 (0.47, 0.88)

 83/129 344  70/127  671 282 BCL2/P46L: MND White 0.70 (0.50, 0.97)

 74/117 363  68/125  649 279 BCL2/P46S: MND White 0.71 (0.52, 0.98)

 81/130 363  74/131  671 275 BCL2/P59S: MND White 0.70 (0.51, 0.96)

 81/128 363  73/130  671 274 BCL2/Q52P: MND White 0.70 (0.51, 0.96)

 85/135 362  77/137  671 272 BCL2/R106H: MND White 0.70 (0.51, 0.94)

 93/140 361  77/135  629 327 NOTCH/G_A1702P: MND White 0.73 (0.55, 0.99)

 97/152 362  82/143  629 295 NOTCH/I1681N: MND White 0.73 (0.55, 0.99)

 97/152 362  82/143  629 295 NOTCH/L1679P: MND White 0.73 (0.55, 0.99)

 97/152 362  82/143  629 295 NOTCH/L1679Q: MND White 0.73 (0.55, 0.99)

 97/152 362  82/143  629 295 NOTCH/P2513L: MND White 0.69 (0.49, 0.96)

 78/122 362  59/108  673 319 NOTCH/P2515FS4: MND White 0.69 (0.51, 0.93)

 99/154 363  81/148  671 304 NOTCH/Q2460X: MND White 0.71 (0.52, 0.98)

 85/131 361  73/127  589 284 NOTCH/X26DEL: MND White 0.75 (0.56, 0.99)

 99/155 363  91/158  649 321 NOTCH/X26INS: MND White 0.74 (0.56, 0.98)

101/159 392  92/160  649 321 NOTCH/X28DEL: MND White 0.75 (0.57, 0.98)

111/169 362  98/167  587 351 NOTCH/X28INS: MND White 0.72 (0.55, 0.94)

115/174 362  99/171  589 352 BCL2/A43G: MND Ann Arbor Stage IV 0.62 (0.41, 0.93)

48/71 309 42/83  495 154 BCL2/C.-11C > T: MND Ann Arbor Stage IV 0.66 (0.46, 0.95)

60/84 309  54/100  471 193 BCL2/E29K: MND Ann Arbor Stage IV 0.60 (0.39, 0.93)

46/67 307 37/73  490 154 BCL2/P59L: MD Ann Arbor Stage IV 0.19 (0.03, 1.00)

3/5 145  8/12  562 149 BCL2/R106H: MND Ann Arbor Stage IV 0.60 (0.40, 0.91)

50/72 307 42/83  490 186 NOTCH/G_A1702P: MND Ann Arbor Stage IV 0.62 (0.42, 0.93)

52/75 287 47/87  487 163 NOTCH/I1681N: MND Ann Arbor Stage IV 0.64 (0.43, 0.94)

52/75 287 48/88  487 163 NOTCH/L1679P: MND Ann Arbor Stage IV 0.64 (0.43, 0.94)

52/75 287 48/88  487 163 NOTCH/L1679Q: MND Ann Arbor Stage IV 0.64 (0.43, 0.94)

52/75 287 48/88  487 163 NOTCH/L2458V: MND Ann Arbor Stage IV 0.65 (0.43, 0.98)

46/68 293 46/86  490 154 NOTCH/P2513L: MND Ann Arbor Stage IV 0.57 (0.36, 0.90)

42/61 307 34/69  629 176 NOTCH/P2515FS4: MND Ann Arbor Stage IV 0.60 (0.40, 0.90)

51/74 293 46/91  495 167 NOTCH/Q2441X: MND Ann Arbor Stage IV 0.65 (0.43, 0.98)

46/68 293 46/85  490 154 NOTCH/Q2460X: MND Ann Arbor Stage IV 0.63 (0.41, 0.96)

43/64 307 41/79  495 156 NOTCH/X26DEL: MND Ann Arbor Stage IV 0.65 (0.45, 0.95)

53/76 317  54/101  490 180 NOTCH/X26INS: MND Ann Arbor Stage IV 0.65 (0.44, 0.94)

54/79 309  54/101  490 180 NOTCH/X28DEL: MND Ann Arbor Stage IV 0.66 (0.46, 0.94)

61/85 307  56/103  483 195 NOTCH/X28INS: MND Ann Arbor Stage IV 0.62 (0.43, 0.89)

64/87 293  57/105  183 196

APPENDIX 3 Pair-Wise Combinations of Markers

The following table outlines the data for all significant pair-wise combinations.

Note: Selected=Biomarker positive, Not Selected=Biomarker negative

APPENDIX 3, TABLE 3.1 Significant Pair-Wise Combinations Median Median OS N N PFS OS Log- Marker Marker Marker Marker N N Un- (Vc − % (Vc − PFS % PFS PFS (Vc − rank A Marker A B Marker B Com- Se- Ex- eval- R vs of R vs Differ- Differ- Logrank PFS R vs P- Type A Level Type B Level bination lected cluded uable R) ITT R) ence ence P-value HR R) value OS HR B_D PSMB1/ C/G Protein CD68 0-50 Selected 118 238 319 N: % in 506d 229 (82.7% P- HR = NAd 0.0550 0.426 NA P11A POSITIVE 57 ITT: vs improve- value = 0.407 vs (0.174- FOLLICULAR vs 17.5% 277d ment) 1e−04 (0.266- NAd 1.046) 61 0.639) B_D PSMB1/ C/G Protein CD68 0-50 Excluded 118 238 319 N: % in 380d −1 (−0.3% P- HR = NAd 0.9645 1.011 NA P11A POSITIVE 118 ITT: vs improve- value = 1.04 vs (0.617- FOLLICULAR vs 35.3% 381d ment) 0.8097 (0.759- NAd 1.658) 120 1.425) B_D PSMB1/ C/G Protein CD68 0-50 Total 118 238 319 N: % in 414d 69 (20% P- HR = NAd 0.3270 0.808 NA P11A POSITIVE 175 ITT: vs improve- value = 0.801 vs (0.527- FOLLICULAR vs 52.7% 345d ment) 0.0855 (0.621- NAd 1.239) 181 1.032) B_D PSMB5/ C/T Protein P65 INTENSITY <=1+ Selected 12 425 238 N: % in 827d 512.5 (163% P- HR = NAd 0.3026 0.333 NA R24C CYTOPLASMIC 5 ITT: vs improve- value = 0.149 vs (0.037- SIGNAL vs 1.8% 314.5d ment) 0.0439 (0.018- 717d 2.994) 7 1.253) B_D PSMB5/ C/T Protein P65 <=1+ Excluded 12 425 238 N: % in 406d 68 (20.1% P- HR = NAd 0.9151 0.979 NA R24C INTENSITY 208 ITT: vs improve- value = 0.803 vs (0.663- CYTOPLASMIC vs 63% 338d ment) 0.0641 (0.637- NAd 1.446) SIGNAL 217 vs 1.013) B_D PSMB5/ C/T Protein P65 <=1+ Total 12 425 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA R24C INTENSITY 213 ITT: vs improve- value = 0.782 vs (0.634- CYTOPLASMIC vs 64.7% 338d ment) 0.0354 (0.622- Nad 1.36) SIGNAL 224 0.984) B_D PSMB1/ C/G Protein 20S % 95-100 Selected 100 330 245 N: % in 576d 288 (100% P- HR = NAd 0.0949 0.516 NA P11A POSITIVE 50 ITT: vs improve- value = 0.543 vs (0.234- CYTOPLASMIC vs 14.8% 288d ment) 0.0145 (0.33- NAd 1.138) SIGNAL 50 0.894) B_D PSMB1/ C/G Protein 20S % 95-100 Excluded 100 330 245 N: % in 355d 9 (2.6% P- HR= NAd 0.5966 1.127 NA P11A POSITIVE 159 ITT: vs improve- value = 0.882 vs (0.723- CYTOPLASMIC vs 48.9% 346d ment) 0.3458 (0.679- NAd 1.758) SIGNAL 171 1.145) B_D PSMB1/ C/G Protein 20S % 95-100 Total 100 330 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA P11A POSITIVE 209 ITT: vs improve- value = 0.785 vs (0.632- CYTOPLASMIC vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) SIGNAL 221 0.989) Clinical PRIORTX 1 Protein CD68 0-50 Selected 132 254 289 N: % in 553d 271 (96.1% P- HR = NAd 0.3616 0.675 POSITIVE 63 ITT: vs improve- value = 0.567 vs (0.288- FOLLICULAR vs 19.6% 282d ment) 0.0129 (0.36- NAd 1.58) 69 0.893) Clinical PRIORTX 1 Protein CD68 0-50 Excluded 132 254 289 N: % in 346d −2 (−0.6% P- HR = NAd 0.6993 0.91 POSITIVE 127 ITT: vs improve- value = 1 vs (0.566- FOLLICULAR vs 37.6% 348d ment) 0.9957 (0.746- NAd 1.466) 127 1.339) Clinical PRIORTX 1 Protein CD68 0-50 Total 132 254 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB1/ C/G Clinical TLAST >1 Selected 146 396 133 N: % in 554d 232 (72% P- HR = NAd 0.8289 1.091 NA P11A year 72 ITT: vs improve- value = 0.615 vs (0.498- vs 21.6% 322d ment) 0.0198 (0.407- NAd 2.391) 74 0.929) B_D PSMB1/ C/G Clinical TLAST >1 Excluded 146 396 133 N: % in 352d 7 (2% P- HR = NAd 0.9430 1.014 NA P11A year 194 ITT: vs improve- value = 0.923 vs (0.694- vs 58.7% 345d ment) 0.512 (0.726- NAd 1.482) 202 1.174) B_D PSMB1/ C/G Clinical TLAST >1 Total 146 396 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A year 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical RACEGRP OTHER Protein 20S % 30-90 Selected 18 445 212 N: % in 346d 232 (203.5% P- HR = 928d 0.7517 1.309 NUCLEAR 11 ITT: vs improve- value = 0.272 vs (0.246- STAINING vs 2.7% 114d ment) 0.032 (0.077- NAd 6.958) 7 0.963) Clinical RACEGRP OTHER Protein 20S % 30-90 Excluded 18 445 212 N: % in 396d 49 (14.1% P- HR = NAd 0.5139 0.879 NUCLEAR 214 ITT: vs improve- value = 0.836 vs (0.598- STAINING vs 65.9% 347d ment) 0.1229 (0.665- NAd 1.293) 231 1.05) Clinical RACEGRP OTHER Protein 20S % 30-90 Total 18 445 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) 238 1.037) B_D PSMB1/ C/G Protein CD68 >50 Selected 52 302 321 N: % in 506d 226 (80.7% P- HR = NAd 0.3998 0.648 NA P11A POSITIVE 24 ITT: vs improve- value = 0.484 vs (0.235- PERI- vs 7.7% 280d ment) 0.0365 (0.241- 1175d 1.791) FOLLICULAR 28 0.971) B_D PSMB1/ C/G Protein CD68 >50 Excluded 52 302 321 N: % in 414d 67 (19.3% P- HR = NAd 0.5170 0.855 NA P11A POSITIVE 150 ITT: vs improve- value = 0.862 vs (0.533- PERI- vs 44.7% 347d ment) 0.2937 (0.653- NAd 1.373) FOLLICULAR 152 1.138) B_D PSMB1/ C/G Protein CD68 >50 Total 52 302 321 N: % in 417d 72 (20.9% P- HR = NAd 0.3311 0.809 NA P11A POSITIVE 174 ITT: vs improve- value = 0.8 vs (0.528- PERI- vs 52.4% 345d ment) 0.0849 (0.619- NAd 1.241) FOLLICULAR 180 1.032) Clinical HITUBD NO Protein CD68 0-50 Selected 132 309 234 N: % in 693d 207 (42.6% P- HR = NAd 0.0204 0.316 OVERALL 64 ITT: vs improve- value = 0.576 vs (0.113- POSITIVE vs 19.6% 486d ment) 0.0177 (0.363- NAd 0.882) 68 0.915) Clinical HITUBD NO Protein CD68 0-50 Excluded 132 309 234 N: % in 346d 59 (20.6% P- HR = NAd 0.6702 1.096 OVERALL 153 ITT: vs improve- value = 0.927 vs (0.718- POSITIVE vs 45.8% 287d ment) 0.5759 (0.712- NAd 1.674) 156 1.207) Clinical HITUBD NO Protein CD68 0-50 Total 132 309 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) B_D PSMB9/ G/G Protein P65 % >0 Selected 63 374 238 N: % in 491d 203 (70.5% P- HR = NAd 0.3042 0.578 NA R60H NUCLEAR 35 ITT: vs improve- value = 0.511 vs (0.2- STAINING vs 9.3% 288d ment) 0.0303 (0.275- NAd 1.667) 28 0.952) B_D PSMB9/ G/G Protein P65 % >0 Excluded 63 374 238 N: % in 367d 22 (6.4% P- HR = NAd 0.9516 1.013 NA R60H NUCLEAR 178 ITT: vs improve- value = 0.85 vs (0.673- STAINING vs 55.4% 345d ment) 0.1982 (0.664- NAd 1.525) 196 1.088) B_D PSMB9/ G/G Protein P65 % >0 Total 63 374 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA R60H NUCLEAR 213 ITT: vs improve- value = 0.782 vs (0.634- STAINING vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) 224 0.984) Clinical HITUBD NO Protein CD68 0-50 Selected 130 256 289 N: % in 624d 203 (48.2% P- HR = NAd 0.0222 0.288 POSITIVE 64 ITT: vs improve- value = 0.604 vs (0.092- FOLLICULAR vs 19.3% 421d ment) 0.031 (0.38- NAd 0.896) 66 096) Clinical HITUBD NO Protein CD68 0-50 Excluded 130 256 289 N: % in 346d 63 (22.3% P- HR = NAd 0.8758 1.037 POSITIVE 126 ITT: vs improve- value = 0.974 vs (0.657- FOLLICULAR vs 37.9% 283d ment) 0.8569 (0.729- NAd 1.636) 130 1.3) Clinical HITUBD NO Protein CD68 0-50 Total 130 256 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 127) 196 1.08) Clinical PRITUX NO Protein CD68 0-50 Selected 159 227 289 N: % in 483d 202 (71.9% P- HR = NAd 0.0713 0.53 POSITIVE 73 ITT: vs improve- value = 0.586 vs (0.262- FOLLICULAR vs 23.6% 281d ment) 0.0066 (0.397- NAd 1.069) 86 0.866) Clinical PRITUX NO Protein CD68 0-50 Excluded 159 227 289 N: % in 346d −3 (−0.9% P- HR = NAd 0.6426 1.134 POSITIVE 117 ITT: vs improve- value = 1.079 vs (0.667- FOLLICULAR vs 33.6% 349d ment) 0.6451 (0.782- NAd 1.928) 110 1.487) Clinical PRITUX NO Protein CD68 0-50 Total 159 227 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB5/ C/T Protein CD68 0-50 Selected 39 317 319 N: % in 417d 197 (89.5% P- HR = NAd 0.0557 0.247 NA R24C POSITIVE 18 ITT: vs improve- value = 0.415 vs (0.052- FOLLICULAR vs 5.8% 220d ment) 0.022 (0.19- NAd 1.165) 21 0.903) B_D PSMB5/ C/T Protein CD68 0-50 Excluded 39 317 319 N: % in 414d 66 (19% P- HR = NAd 0.7320 0.924 NA R24C POSITIVE 157 ITT: vs improve- value = 0.849 vs (0.587- FOLLICULAR vs 47% 348d ment) 0.2328 (0.648- NAd 1.454) 160 1.112) B_D PSMB5/ C/T Protein CD68 0-50 Total 39 317 319 N: % in 414d 69 (20% P- HR = NAd 0.3270 0.808 NA R24C POSITIVE 175 ITT: vs improve- value = 0.801 vs (0.527- FOLLICULAR vs 52.7% 345d ment) 0.0855 (0.621- NAd 1.239) 181 1.032) B_D PSMB1/ C/G Clinical AGEGRP <=65 Selected 182 360 133 N: % in 464d 185 (66.3% P- HR = NAd 0.5650 0.822 NA P11A 86 ITT: vs improve- value = 0.605 vs (0.421- vs 27% 279d ment) 0.0071 (0.418- NAd 1.605) 96 0.875) B_D PSMB1/ C/G Clinical AGEGRP <=65 Excluded 182 360 133 N: % in 355d 7 (2% P- HR = NAd 0.6392 1.1 NA P11A 180 ITT: vs improve- value = 0.962 vs (0.738- vs 53.3% 348d ment) 0.766 (0.748- NAd 1.64) 180 1.238) B_D PSMB1/ C/G Clinical AGEGRP <=65 Total 182 360 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A 266 ITT: vs improve- value = 0.828 vs 0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical SEX MALE Protein 20S % 30-90 Selected 111 352 212 N: % in 415d 180 (76.6% P- HR = NAd 0.0324 0.482 NUCLEAR 63 ITT vs improve- value = 0.534 vs (0.243- STAINING vs 16.4% 235d ment) 0.005 (0.342- 1263d 0.955) 48 0.832) Clinical SEX MALE Protein 20S % 30-90 Excluded 111 352 212 N: % in 360d 3 (0.8% P- HR = NAd 0.5157 1.16 NUCLEAR 162 ITT: vs improve- value = 0.903 vs (0.742- STAINING vs 52.1% 357d ment) 0.4394 (0.697- NAd 1.813) 190 1.169) Clinical SEX MALE Protein 20S % 30-90 Total 111 352 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING vs 68.6% 345d ment) 0.1 (0.665- NAd 1336) 238 1.037) B_D PSMB1/ G/G B_D PSMB5/ C/T Selected 14 528 133 N: % in 417d 179.5 (75.6% P- HR = 1037d 0.6740 0.6 NA P11A NA R24C 7 ITT: vs improve- value = 0.18 vs (0.054- vs 2.1% 237.5d ment) 0.0221 (0.035- NAd 6.662) 7 0.921) B_D PSMB1/ G/G B_D PSMB5/ C/T Excluded 14 528 133 N: % in 414d 69 (20% P- HR = NAd 0.7952 1.047 NA P11A NA R24C 259 ITT: vs improve- value = 0.845 vs (0.741- vs 78.2% 345d ment) 0.1175 (0.685- NAd 1.479) 269 1.043) B_D PSMB1/ G/G B_D PSMB5/ C/T Total 14 528 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A NA R24C 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) B_D PSMB1/ C/G Protein P27 % 0-70 Selected 110 320 245 N: % in 444d 167 (60.3% P- HR = NAd 0.3082 0.67 NA P11A NUCLEI 53 ITT: vs improve- value = 0.456 vs (0.307- POSITIVE vs 16.3% 277d ment) 7e−04 (0.286- NAd 1.459) 57 0.727) B_D PSMB1/ C/G Protein P27 % 0-70 Excluded 110 320 245 N: % in 360d 12 (3.4% P- HR = NAd 0.9580 0.988 NA P11A NUCLEI 158 ITT: vs improve- value = 0.9 vs (0.637- POSITIVE vs 47.4% 348d ment) 0.4399 (0.689- NAd 1.532) 162 1.176) B_D PSMB1/ C/G Protein P27 % 0-70 Total 110 320 245 N: % in 396d 58 (17.2% P- HR = NAd 0.5987 0.903 NA P11A NUCLEI 211 ITT: vs improve- value = 0.777 vs (0.617- POSITIVE vs 63.7% 338d ment) 0.0319 (0.617- NAd 1.322) 219 0.979) B_D PSMB1/ C/G Protein P27 SIGNAL >=2+ Selected 155 275 245 N: % in 444d 164 (58.6% P- HR = NAd 0.3831 0.749 NA P11A INTENSITY 75 ITT: vs improve- value = 0.593 vs (0.391- vs 23% 280d ment) 0.0085 (0.4- NAd 1.436) 80 0.879) B_D PSMB1/ C/G Protein P27 SIGNAL >=2+ Excluded 155 275 245 N: % in 352d 6 (1.6999- P- HR = NAd 0.9691 0.991 NA P11A INTENSITY 136 ITT: vs 999999- value = 0.897 vs (0.618- vs 40.7% 346d 9999% 0.4562 (0.674- NAd 1.589) 139 improve- 1.194) ment) B_D PSMB1/ C/G Protein P27 SIGNAL >=2+ Total 155 275 245 N: % in 396d 58 (17.2% P- HR = NAd 0.5987 0.903 NA P11A INTENSITY 211 ITT: vs improve- value = 0.777 vs (0.617- vs 63.7% 338d ment) 0.0319 (0.617- NAd 1.322) 219 0.979) Clinical TLAST >1 year Protein CD68 0-50 Selected 176 210 289 N: % in 519d 162 (45.4% P- HR = NAd 0.2048 0.587 POSITIVE 86 ITT: vs improve- value = 0.633 vs (0.256- FOLLICULAR vs 26.1% 357d ment) 0.0185 (0.431- NAd 1.35) 90 0.929) Clinical TLAST >1 year Protein CD68 0-50 Excluded 176 210 289 N: % in 346d 58 (20.1% P- HR = NAd 0.7189 0.915 POSITIVE 104 ITT: vs improve- value = 1.038 vs (0.565- FOLLICULAR vs 31.1% 288d ment) 0.8222 (0.755- NAd 1.483) 106 1.428) Clinical TLAST >1 year Protein CD68 0-50 Total 176 210 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB1/ C/G Protein 20S % 30-90 Selected 108 322 245 N: % in 431d 156 (56.7% P- HR = NAd 0.1377 0.54 NA P11A NUCLEAR 45 ITT: vs improve- value = 0.621 vs (0.236- STAINING vs 16% 275d ment) 0.0428 (0.39- NAd 1.234) 63 0.989) B_D PSMB1/ C/G Protein 20S % 30-90 Excluded 108 322 245 N: % in 380d 34 (9.8% P- HR = NAd 0.6667 1.104 NA P11A NUCLEAR 164 ITT: vs improve- value = 0.849 vs (0.704- STAINING vs 47.7% 346d ment) 0.231 (0.65- NAd 1.729) 158 1.11) B_D PSMB1/ C/G Protein 20S % 30-90 Total 108 322 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA P11A NUCLEAR 209 ITT: vs improve- value = 0.785 vs (0.632- STAINING vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) 221 0.989) Clinical AGEGRP <=65 Protein CD68 0-50 Selected 215 171 289 N: % in 429d 154 (56% P- HR = NAd 0.1020 0.62 POSITIVE 102 ITT: vs improve- value = 0.57 vs (0.348- FOLLICULAR vs 31.9% 275d ment) 8e−04 (0.408- NAd 1.105) 113 0.797) Clinical AGEGRP <=65 Protein CD68 0-50 Excluded 215 171 289 N: % in 348d −79 (−18.5% P- HR = NAd 0.5681 1.196 POSITIVE 88 ITT: vs improve- value = 1.383 vs (0.646- FOLLICULAR vs 25.3% 427d ment) 0.0837 (0.955- NAd 2.217) 83 2.003) Clinical AGEGRP <=65 Protein CD68 0-50 Total 215 171 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB1/ C/G Protein P65 % >90% Selected 157 280 238 N: % in 431d 153 (55% P- HR = NAd 0.2892 0.7 NA P11A POSITIVE 75 ITT: vs improve- value = 0.574 vs (0.361- CYTOPLASMIC vs 23.3% 278d ment) 0.0048 (0.389- NAd 1.358) SIGNAL 82 0.848) B_D PSMB1/ C/G Protein P65 % >90% Excluded 157 280 238 N: % in 355d 7 (2% P- HR = NAd 0.7743 1.071 NA P11A POSITIVE 138 ITT: vs improve- value = 0.909 vs (0.67- CYTOPLASMIC vs 41.5% 348d ment) 0.513 (0.684- NAd 1.712) SIGNAL 142 1.209) B_D PSMB1/ C/G Protein P65 % >90% Total 157 280 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA P11A POSITIVE 213 ITT: vs improve- value = 0.782 vs (0.634- CYTOPLASMIC vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) SIGNAL 224 0.984) B_D PSMB9/ A/G Protein 20S % 95-100 Selected 89 341 245 N: % in 426d 153 (56% P- HR = NAd 0.2901 0.659 NA R60H POSITIVE 45 ITT: vs improve- value = 0.544 vs (0.302- CYTOPLASMIC vs 13.2% 273d ment) 0.0222 (0.32- NAd 1.436) SIGNAL 44 0.925) B_D PSMB9/ A/G Protein 20S % 95-100 Excluded 89 341 245 N: % in 396d 49 (14.1% P- HR = NAd 0.9020 1.028 NA R60H POSITIVE 164 ITT: vs improve- value = 0.855 vs (0.659- CYTOPLASMIC vs 50.5% 347d ment) 0.2336 (0.661- NAd 1.603) SIGNAL 177 1.106) B_D PSMB9/ A/G Protein 20S % 95-100 Total 89 341 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA R60H POSITIVE 209 ITT: vs improve- value = 0.785 vs (0.632- CYTOPLASMIC vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) SIGNAL 221 0.989) B_D PSMB1/ C/G Protein 20S <=2+ Selected 108 322 245 N: % in 431d 153 (55% P- HR = NAd 0.4710 0.724 NA P11A INTENSITY 55 ITT: vs improve- value = 0.601 vs (0.3- CYTOPLASMIC vs 16% 278d ment) 0.0269 (0.381- NAd 1.749) SIGNAL 53 0.948) B_D PSMB1/ C/G Protein 20S <=2+ Excluded 108 322 245 N: % in 380d 35 (10.1% P- HR = NAd 0.9958 0.999 NA P11A INTENSITY 154 ITT: vs improve- value = 0.852 vs (0.651- CYTOPLASMIC vs 47.7% 345d ment) 0.2403 (0.651- NAd 1.533) SIGNAL 168 1.114) B_D PSMB1/ C/G Protein 20S <=2+ Total 108 322 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA P11A INTENSITY 209 ITT: vs improve- value = 0.785 vs (0.632- CYTOPLASMIC vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) SIGNAL 221 0.989) B_D PSMB9/ A/G Protein CD68 0-50 Selected 104 252 319 N: % in 426d 153 (56% P- HR = NAd 0.1848 0.537 NA R60H POSITIVE 51 ITT: vs improve- value = 0.592 vs (0.211- FOLLICULAR vs 15.4% 273d ment) 0.0339 (0.362- NAd 1.366) 53 0.968) B_D PSMB9/ A/G Protein CD68 0-50 Excluded 104 252 319 N: % in 414d 65 (18.6% P- HR = NAd 0.7690 0.93 NA R60H POSITIVE 124 ITT: vs improve- value = 0.888 vs (0.574- FOLLICULAR vs 37.3% 349d ment) 0.435 (0.659- NAd 1.508) 128 1.197) B_D PSMB9/ A/G Protein CD68 0-50 Total 104 252 319 N: % in 414d 69 (20% P- HR = NAd 0.3270 0.808 NA R60H POSITIVE 175 ITT: vs improve- value = 0.801 vs (0.527- FOLLICULAR vs 52.7% 345d ment) 0.0855 (0.621- NAd 1.239) 181 1.032) B_D PSMB9/ G/G Protein 20S % 30-90 Selected 145 285 245 N: % in 431d 151 (53.9% P- HR = NAd 0.2782 0.702 NA R60H NUCLEAR 74 ITT: vs improve- value = 0.647 vs (0.368- STAINING vs 21.5% 280d ment) 0.0262 (0.439- NAd 1.336) 71 0.953) B_D PSMB9/ G/G Protein 20S % 30-90 Excluded 145 285 245 N: % in 360d 15 (4.2999- P- HR = NAd 0.7758 1.073 NA R60H NUCLEAR 135 ITT: vs 999999- value = 0.86 vs (0.661- STAINING vs 42.2% 345d 9999% 0.3045 (0.644- NAd 1.741) 150 improve- 1.148) ment) B_D PSMB9/ G/G Protein 20S % 30-90 Total 145 285 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA R60H NUCLEAR 209 ITT: vs improve- value = 0.785 vs (0.632- STAINING vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) 221 0.989) Protein CD68 0-50 Protein P65 % >90% Selected 250 136 289 N: % in 429d 150 (53.8% P- HR = NAd 0.0605 0.593 POSITIVE POSITIVE 114 ITT: vs improve- value = 0.616 vs (0.342- FOLLICULAR CYTOPLASMIC vs 37% 279d ment) 0.0019 (0.452- NAd 1.029) SIGNAL 136 0.839) Protein CD68 0-50 Protein P65 % >90% Excluded 250 136 289 N: % in 324d −162 (−33.3% P- HR = NAd 0.3261 1.408 POSITIVE POSITIVE 76 ITT: vs improve- value = 1.52 vs (0.709- FOLLICULAR CYTOPLASMIC vs 20.1% 486d ment) 0.0545 (0.989- NAd 2.795) SIGNAL 60 2.335) Protein CD68 0-50 Protein P65 % >90% Total 250 136 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR CYTOPLASMIC vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) SIGNAL 196 1.08) Clinical AGEGRP <=65 Protein CD68 0-50 Selected 177 207 291 N: % in 431d 150 (53.4% P- HR = NAd 0.7612 0.91 POSITIVE 89 ITT: vs improve- value = 0.663 vs (0.496- PERI- vs 26.2% 281d ment) 0.0274 (0.458- NAd 1.67) FOLLICULAR 88 0.959) Clinical AGEGRP <=65 Protein CD68 0-50 Excluded 177 207 291 N: % in 348d −3 (−0.9% P- HR = NAd 0.3903 0.779 POSITIVE 100 ITT: vs improve- value = 1.027 vs (0.44- PERI- vs 30.7% 351d ment) 0.874 (0.739- NAd 1.379) FOLLICULAR 107 1.428) Clinical AGEGRP <=65 Protein CD68 0-50 Total 177 207 291 N: % in 406d 60 (17.3% P- HR = NAd 0.4116 0.841 POSITIVE 189 ITT: vs improve- value = 0.845 vs (0.555- PERI- vs 56.9% 346d ment) 0.1772 (0.662- NAd 1.273) FOLLICULAR 195 1.08) Clinical TLAST >1 year Protein P65 % >90% Selected 229 241 205 N: % in 506d 149 (41.7% P- HR = NAd 0.3300 0.713 POSITIVE 112 ITT: vs improve- value = 0.698 vs (0.36- CYTOPLASMIC vs 33.9% 357d ment) 0.0331 (0.5- NAd 1.413) SIGNAL 117 0.973) Clinical TLAST >1 year Protein P65 % >90% Excluded 229 241 205 N: % in 345d 65 (23.2% P- HR = NAd 0.9927 1.002 POSITIVE 117 ITT: vs improve- value = 0.941 vs (0.644- CYTOPLASMIC vs 35.7% 280d ment) 0.6849 (0.699- NAd 1.557) SIGNAL 124 1.266) Clinical TLAST >1 year Protein P65 % >90% Total 229 241 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) B_D PSMB1/ C/G Protein CD68 0-50 Selected 129 280 266 N: % in 426d 148 (53.2% P- HR = NAd 0.2690 0.647 NA P11A OVERALL 64 ITT: vs improve- value = 0.525 vs (0.297- POSITIVE vs 19.1% 278d ment) 0.0025 (0.343- NAd 1.409) 65 0.804) B_D PSMB1/ C/G Protein CD68 0-50 Excluded 129 280 266 N: % in 355d 7 (2% P- HR = NAd 0.9914 1.002 NA P11A OVERALL 137 ITT: vs improve- value = 0.894 vs (0.633- POSITIVE vs 41.5% 348d ment) 0.4433 (0.672- NAd 1.587) 143 1.191) B_D PSMB1/ C/G Protein CD68 0-50 Total 129 280 266 N: % in 396d 51 (14.8% P- HR = NAd 0.5159 0.877 NA P11A OVERALL 201 ITT: vs improve- value = 0.768 vs (0.591- POSITIVE vs 60.6% 345d ment) 0.0281 (0.606- NAd 1.302) 208 0.973) Protein CD68 0-50 Protein CD68 0-50 Selected 193 191 291 N: % in 429d 147 (52.1% P- HR = NAd 0.0947 0.596 POSITIVE POSITIVE 94 ITT: vs improve- value = 0.625 vs (0.323- FOLLICULAR PERI- vs 28.6% 282d ment) 0.0075 (0.441- NAd 1.101) FOLLICULAR 99 0.885) Protein CD68 0-50 Protein CD68 0-50 Excluded 193 191 291 N: % in 344d −7 (−2% P- HR = NAd 0.6374 1.148 POSITIVE POSITIVE 95 ITT: vs improve- value = 1.098 vs (0.647- FOLLICULAR PERI- vs 28.3% 351d ment) 0.5972 (0.775- NAd 2.036) FOLLICUI.AR 96 1.556) Protein CD68 0-50 Protein CD68 0-50 Total 193 191 291 N: % in 406d 60 (17.3% P- HR = NAd 0.4116 0.841 POSITIVE POSITIVE 189 ITT: vs improve- value = 0.845 vs (0.555- FOLLICULAR PERI- vs 56.9% 346d ment) 0.1772 (0.662- NAd 1.273) FOLLICULAR 195 1.08) Clinical FLIPI High Protein P27 % 0-70 Selected 113 350 212 N: % in 358d 146 (68.9% P- HR = 1103d 0.8099 0.934 NUCLEI 53 ITT: vs improve- value = 0.588 vs (0.539- POSITIVE vs 16.7% 212d ment) 0.0156 (0.381- 1111d 1.619) 60 0.908) Clinical FLIPI High Protein P27 % 0-70 Excluded 113 350 212 N: % in 406d 55 (15.7% P- HR = NAd 0.5519 0.859 NUCLEI 174 ITT: vs improve- value = 0.905 vs (0.522- POSITIVE vs 51.9% 351d ment) 0.4522 (0.698- NAd 1.416) 176 1.174) Clinical FLIPI High Protein P27 % 0-70 Total 113 350 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 NUCLEI 227 ITT: vs improve- value = 0.822 vs (0.62- POSITIVE vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Clinical SEX MALE Protein P65 % >90% Selected 169 301 205 N: % in 414d 143 (52.8% P- HR = NAd 0.0574 0.571 POSITIVE 97 ITT: vs improve- value = 0.622 vs (0.317- CYTOPLASMIC vs 25% 271d ment) 0.0094 (0.433- NAd 1.025) SIGNAL 72 0.894) Clinical SEX MALE Protein P65 % >90% Excluded 169 301 205 N: % in 355d −20 (−5.3% P- HR = NAd 0.4521 1.2 POSITIVE 132 ITT: vs improve- value = 0.9 vs (0.746- CYTOPLASMIC vs 44.6% 375d ment) 0.4653 (0.678- NAd 1.931) SIGNAL 169 1.194) Clinical SEX MALE Protein P65 % >90% Total 169 301 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) B_D PSMB1/ C/G B_D PSMB9/ G/G Selected 150 392 133 N: % in 431d 143 (49.7% P- HR = NAd 0.7239 0.888 NA P11A NA R60H 66 ITT: vs improve- value = 0.65 vs (0.458- vs 22.2% 288d ment) 0.0335 (0.436- NAd 1.722) 84 0.97) B_D PSMB1/ C/G B_D PSMB9/ G/G Excluded 150 392 133 N: % in 380d 34 (9.8% P- HR = NAd 0.6731 1.09 NA P11A NA R60H 200 ITT: vs improve- value = 0.906 vs (0.73- vs 58.1% 346d ment) 0.4293 (0.71- NAd 1.629) 192 1.157) B_D PSMB1/ C/G B_D PSMB9/ G/G Total 150 392 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A NA R60H 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical AGEGRP <=65 Protein P27 % 0-70 Selected 194 269 212 N: % in 422d 143 (51.3% P- HR = NAd 0.8473 0.946 NUCLEI 93 ITT: vs improve- value = 0.7 vs (0.54- POSITIVE vs 28.7% 279d ment) 0.0458 (0.493- NAd 1.658) 101 0.996) Clinical AGEGRP <=65 Protein P27 % 0-70 Excluded 194 269 212 N: % in 352d 4 (1.0999- P- HR = NAd 0.5476 0.86 NUCLEI 134 ITT: vs 999999- value = 0.923 vs (0.526- POSITIVE vs 39.9% 348d 9999% 0.5904 (0.693- NAd 1.406) 135 improve- 1.231) ment) Clinical AGEGRP <=65 Protein P27 % 0-70 Total 194 269 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 NUCLEI 227 ITT: vs improve- value = 0.822 vs (0.62- POSITIVE vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Protein 20S % 30-90 Protein 20S >=3+ Selected 153 310 212 N: % in 422d 142 (50.7% P- HR = NAd 0.0906 0.568 NUCLEAR INTENSITY 79 ITT: vs improve- value = 0.681 vs (0.292- STAINING CYTOPLASMIC vs 22.7% 280d ment) 0.0462 (0.467- NAd 1.103) SIGNAL 74 0.994) Protein 20S % 30-90 Protein 20S >=3+ Excluded 153 310 212 N: % in 351d 4 (1.2% P- HR = NAd 0.5534 1.148 NUCLEAR INTENSITY 146 ITT: vs improve- value = 0.921 vs (0.727- STAINING CYTOPLASMIC vs 45.9% 347d ment) 0.5581 (0.7- NAd 1.815) SIGNAL 164 1.213) Protein 20S % 30-90 Protein 20S >=3+ Total 153 310 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR INTENSITY 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING CYTOPLASMIC vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) SIGNAL 238 1.037) B_D PSMB9/ A/G Protein CD68 0-50 Selected 112 297 266 N: % in 414d 141 (51.6% P- HR = NAd 0.2509 0.61 NA R60H OVERALL 56 ITT: vs improve- value = 0.501 vs (0.26- POSITIVE vs 16.6% 273d ment) 0.0031 (0.313- NAd 1.43) 56 0.8) B_D PSMB9/ A/G Protein CD68 0-50 Excluded 112 297 266 N: % in 358d 9 (2.6% P- HR = NAd 0.9776 1.006 NA R60H OVERALL 145 ITT: vs improve- value = 0.876 vs (0.644- POSITIVE vs 44% 349d ment) 0.3488 (0.665- NAd 1.573) 152 1.155) B_D PSMB9/ A/G Protein CD68 0-50 Total 112 297 266 N: % in 396d 51 (14.8% P- HR = NAd 0.5159 0.877 NA R60H OVERALL 201 ITT: vs improve- value = 0.768 vs (0.591- POSITIVE vs 60.6% 345d ment) 0.0281 (0.606- NAd 1.302) 208 0.973) B_D PSMB5/ C/C Protein 20S % 30-90 Selected 199 231 245 N: % in 422d 141 (50.2% P- HR = NAd 0.6988 0.896 NA R24C NUCLEAR 95 ITT: vs improve- value = 0.701 vs (0.513- STAINING vs 29.5% 281d ment) 0.0385 (0.5- NAd 1.563) 104 0.983) B_D PSMB5/ C/C Protein 20S % 30-90 Excluded 199 231 245 N: % in 355d 9 (2.6% P- HR = NAd 0.8760 0.958 NA R24AC NUCLEAR 114 ITT: vs improve- value = 0.869 vs (0.562- STAINING vs 34.2% 346d ment) 0.384 (0.633- NAd 1.635) 117 1.193) B_D PSMB5/ C/C Protein 20S % 30-90 Total 199 231 245 N: % in 406d 61 (17.7% P- HR = NAd 0.7080 0.929 NA R24C NUCLEAR 209 ITT: vs improve- value = 0.785 vs (0.632- STAINING vs 63.7% 345d ment) 0.0397 (0.624- NAd 1.365) 221 0.989) B_D PSMB1/ C/G Clinical ANNARBOR >=III Selected 199 343 133 N: % in 415d 140 (50.9% P- HR = NAd 0.7606 0.92 NA P11A 96 ITT: vs improve- value = 0.639 vs (0.536- vs 29.5% 275d ment) 0.0076 (0.459- NAd 1.577) 103 0.89) B_D PSMB1/ C/G Clinical ANNARBOR >=III Excluded 199 343 133 N: % in 414d 39 (10.4% P- HR = NAd 0.6663 1.102 NA P11A 170 ITT: vs improve- value = 0.931 vs (0.708- vs 50.8% 375d ment) 0.6023 (0.712- NAd 1.716) 173 1.218) B_D PSMB1/ C/G Clinical ANNARBOR >=III Total 199 343 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical FLIPI High Protein P65 % >90% Selected 160 310 205 N: % in 352d 140 (66% P- HR = 1343d 0.4043 0.808 POSITIVE 77 ITT: vs improve- value = 0.644 vs (0.49- CYTOPLASMIC vs 23.7% 212d ment) 0.0168 (0.448- 1263d 1.333) SIGNAL 83 0.926) Clinical FLIPI High Protein P65 % >90% Excluded 160 310 205 N: % in 429d 51 (13.5% P- HR = NAd 0.8360 1.06 POSITIVE 152 ITT: vs improve- value = 0.919 vs (0.612- CYTOPLASMIC vs 45.9% 378d ment) 0.5531 (0.695- NAd 1.836) SIGNAL 158 1.215) Clinical FLIPI High Protein P65 % >90% Total 160 310 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Clinical AGEGRP <=65 Protein P65 % >90% Selected 296 174 205 N: % in 415d 138 (49.8% P- HR = NAd 0.6825 0.907 POSITIVE 142 ITT: vs improve- value = 0.684 vs (0.569- CYTOPLASMIC vs 43.9% 277d ment) 0.0078 (0.515- NAd 1.447) SIGNAL 154 0.906) Clinical AGEGRP <=65 Protein P65 % >90% Excluded 296 174 205 N: % in 352d −62 (−15% P- HR = NAd 0.8391 0.94 POSITIVE 87 ITT: vs improve- value = 1.159 vs (0.513- CYTOPLASMIC vs 25.8% 414d ment) 0.4179 (0.809- NAd 1.721) SIGNAL 87 1.66) Clinical AGEGRP <=65 Protein P65 % >90% Total 296 174 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Protein 20S % 30-90 Protein P65 % >90% Selected 232 231 212 N: % in: 414d 137 (49.5% P- HR = NAd 0.5718 0.86 NUCLEAR POSITIVE 109 ITT: vs improve- value = 0.7 vs (0.509- STAINING CYTOPLASMIC vs 34.4% 277d ment) 0.0249 (0.512- NAd 1.451) SIGNAL 123 0.957) Protein 20S % 30-90 Protein P65 % >90% Excluded 232 231 212 N: % in 351d −68 (−16.2% P- HR = NAd 0.9292 0.976 NUCLEAR POSITIVE 116 ITT: vs improve- value = 0.983 vs (0.571- STAINING CYTOPLASMIC vs 34.2% 419d ment) 0.9146 (0.714- NAd 1.668) SIGNAL 115 1.353) Protein 20S % 30-90 Protein P65 % >90% Total 232 231 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR POSITIVE 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING CYTOPLASMIC vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) SIGNAL 238 1.037) B_D PSMB1/ C/G Protein P65 % 0 Selected 144 293 238 N: % in 415d 136 (48.7% P- HR = NAd 0.5700 0.825 NA P11A NUCLEAR 70 ITT: vs improve- value = 0.641 vs (0.424- STAINING vs 21.3% 279d ment) 0.0243 (0.434- NAd 1.605) 74 0.947) B_D PSMB1/ C/G Protein P65 % 0 Excluded 144 293 238 N: % in 406d 60 (17.3% P- HR = NAd 0.9159 0.975 NA P11A NUCLEAR 143 ITT: vs improve- value = 0.853 vs (0.612- STAINING vs 43.4% 346d ment) 0.2722 (0.642- NAd 1.554) 150 1.133) B_D PSMB1/ C/G Protein P65 % 0 Total 144 293 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA P11A NUCLEAR 213 ITT: vs improve- value = 0.782 vs (0.634- STAINING vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) 224 0.984) Protein CD68 0-50 Protein P65 % >90% Selected 255 185 235 N: % in 414d 135 (48.4% P- HR = NAd 0.3681 0.798 OVERALL POSITIVE 126 ITT: vs improve- value = 0.671 vs (0.488- POSITIVE CYTOPLASMIC vs 37.8% 279d ment) 0.0086 (0.498- NAd 1.305) SIGNAL 129 0.906) Protein CD68 0-50 Protein P65 % >90% Excluded 255 185 235 N: % in 352d −23 (−6.1% P- HR = NAd 0.8468 1.062 OVERALL POSITIVE 90 ITT: vs improve- value = 1.052 vs (0.575- POSITIVE CYTOPLASMIC vs 27.4% 375d ment) 0.7752 (0.736- NAd 1.96) SIGNAL 95 1.503) Protein CD68 0-50 Protein P65 % >90% Total 255 185 235 N: % in 366d 21 (6.1% P- HR = NAd 0.5608 0.892 OVERALL POSITIVE 216 ITT: vs improve- value = 0.814 vs (0.608- POSITIVE CYTOPLASMIC vs 65.2% 345d ment) 0.0769 (0.648- NAd 1.309) SIGNAL 224 1.023) Clinical AGEGRP <=65 Protein CD68 0-50 Selected 226 215 234 N: % in 414d 135 (48.4% P- HR = NAd 0.7470 0.915 OVERALL 115 ITT: vs improve- value = 0.658 vs (0.533- POSITIVE vs 33.5% 279d ment) 0.0104 (0.476- NAd 1.569) 111 0.909) Clinical AGEGRP <=65 Protein CD68 0-50 Excluded 226 215 234 N: % in 352d 1 (0.2999- P- HR = NAd 0.5974 0.863 OVERALL 102 ITT: vs 9999999- value = 1.03 vs (0.499- POSITIVE vs 31.9% 351d 9989% 0.8542 (0.745- NAd 1.492) 113 improve- 1.424) ment) Clinical AGEGRP <=65 Protein CD68 0-50 Total 226 215 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) Clinical PRITUX NO Protein P65 % 0 Selected 194 276 205 N: % in 422d 135 (47% P- HR = NAd 0.6357 0.877 NUCLEAR 92 ITT: vs improve- value = 0.702 vs (0.511- STAINING vs 28.7% 287d ment) 0.0407 (0.5- NAd 1.508) 102 0.987) Clinical PRITUX NO Protein P65 % 0 Excluded 194 276 205 N: % in 351d 5 (1.4% P- HR = NAd 0.9900 0.997 NUCLEAR 137 ITT: vs improve- value = 0.942 vs (0.601- STAINING vs 40.9% 346d ment) 0.6871 (0.703- NAd 1.653) 139 1.262) Clinical PRITUX NO Protein P65 % 0 Total 194 276 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 NUCLEAR 229 ITT: vs improve- value = 0.826 vs (0.636- STAINING vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) 241 1.03) Clinical TLAST >1 year Protein CD68 0-50 Selected 189 252 234 N: % in 483d 135 (38.8% P- HR = NAd 0.4895 0.789 OVERALL 99 ITT: vs improve- value = 0.695 vs (0.402- POSITIVE vs 28% 348d ment) 0.0451 (0.486- NAd 1.549) 90 0.994) Clinical TLAST >1 year Protein CD68 0-50 Excluded 189 252 234 N: % in 347d 59 (20.5% P- HR = NAd 0.8742 0.963 OVERALL 118 ITT: vs improve- value = 0.944 vs (0.604- POSITIVE vs 37.3% 288d ment) 0.7048 (0.702- NAd 1.534) 134 1.27) Clinical TLAST >1 year Protein CD68 0-50 Total 189 252 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) Protein CD68 0-50 Protein CD68 0-50 Selected 231 155 289 N: % in 414d 133 (47.3% P- HR = NAd 0.0725 0.604 OVERALL POSITIVE 113 ITT: vs improve- value = 0.63 vs (0.346- POSITIVE FOLLICULAR vs 34.2% 281d ment) 0.0037 (0.459- NAd 1.053) 118 0.863) Protein CD68 0-50 Protein CD68 0-50 Excluded 231 155 289 N: % in 380d −1 (−0.3% P- HR = NAd 0.3788 1.331 OVERALL POSITIVE 77 ITT: vs improve- value = 1.254 vs (0.702- POSITIVE FOLLICULAR vs 23% 381d ment) 0.257 (0.846- NAd 2.524) 78 1.858) Protein CD68 0-50 Protein CD68 0-50 Total 231 155 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 OVERALL POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- POSITIVE FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Protein CD68 0-50 Protein P65 >=2+ Selected 242 144 2S9 N: % in 414d 133 (47.3% P- HR = NAd 0.0511 0.58 POSITIVE INTENSITY 114 ITT: vs improve- value = 0.653 vs (0.333- FOLLICULAR CYTOPLASMIC vs 35.9% 281d ment) 0.0064 (0.48- NAd 1.009) SIGNAL 128 0.89) Protein CD68 0-50 Protein P65 >=2+ Excluded 242 144 289 N: % in 351d −88 (−20% P- HR = NAd 0.2917 1.432 POSITIVE INTENSITY 76 ITT: vs improve- value = 1.334 vs (0.732- FOLLICULAR CYTOPLASMIC vs 21.3% 439d ment) 0.1744 (0.879- NAd 2.8) SIGNAL 68 2.024) Protein CD68 0-50 Protein P65 >=2+ Total 242 144 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE INTENSITY 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR CYTOPLASMIC vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) SIGNAL 196 1.08) B_D PSMB9/ A/G Protein P65 % >90% Selected 130 307 238 N: % in 406d 133 (48.7% P- HR = NAd 0.1673 0.589 NA R60H POSITIVE 64 ITT: vs improve- value = 0.616 vs (0.275- CYTOPLASMIC vs 19.3% 273d ment) 0.0268 (0.4- NAd 1.26) SIGNAL 66 0.95) B_D PSMB9/ A/G Protein P65 % >90% Excluded 130 307 238 N: % in 414d 66 (19% P- HR = NAd 0.6468 1.11 NA R60H POSITIVE 149 ITT: vs improve- value = 0.853 vs (0.711- CYTOPLASMIC vs 45.5% 348d ment) 0.2491 (0.65- NAd 1.73) SIGNAL 158 1.118) B_D PSMB9/ A/G Protein P65 % >90% Total 130 307 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA R60H POSITIVE 213 ITT: vs improve- value = 0.782 vs (0.634- CYTOPLASMIC vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) SIGNAL 224 0.984) Protein CD68 0-50 Protein P27 SIGNAL >=2+ Selected 251 135 289 N: % in 414d 132 (46.8% P- HR = NAd 0.0695 0.612 POSITIVE INTENSITY 121 ITT: vs improve- value = 0.651 vs (0.359- FOLLICULAR vs 37.2% 282d ment) 0.0058 (0.479- NAd 1.045) 130 0.885) Protein CD68 0-50 Protein P27 SIGNAL >=2+ Excluded 251 135 289 N: % in 351d −114 (−24.5% P- HR = NAd 0.2852 1.46 POSITIVE INTENSITY 69 ITT: vs improve- value = 1.363 vs (0.726- FOLLICULAR vs 20% 465d ment) 0.1445 (0.898- NAd 2.936) 66 2.07) Protein CD68 0-50 Protein P27 SIGNAL >=2+ Total 251 135 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE INTENSITY 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Clinical FLIPI High Protein CD68 0-50 Selected 119 267 289 N: % in 347d 127 (57.7% P- HR = NAd 0.2401 0.692 POSITIVE 53 ITT: vs improve- value = 0.655 vs (0.374- FOLLICULAR vs 17.6% 220d ment) 0.0481 (0.429 1263d 1.282 66 -1) Clinical FLIPI High Protein CD68 0-50 Excluded 119 267 289 N: % in 431d 50 (13.1% P- HR = NAd 0.8997 1.038 POSITIVE 137 ITT: vs improve- value = 0.974 vs (0.585- FOLLICULAR vs 39.6% 381d ment) 0.8607 (0.72- NAd 1.841) 130 1.318) Clinical FLIPI High Protein CD68 0-50 Total 119 267 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB9/ G/G Clinical AGEGRP <=65 Selected 232 310 133 N: % in 456d 126 (38.2% P- HR = NAd 0.9809 0.993 NA R60H 113 ITT: vs improve- value = 0.706 vs (0.574- vs 34.4% 330d ment) 0.032 (0.513- NAd 1.72) 119 0.972) B_D PSMB9/ G/G Clinical AGEGRP <=65 Excluded 232 310 133 N: % in 355d 10 (2.8999- P- HR = NAd 0.8407 1.046 NA R60H 153 ITT: vs 999999- value = 0.931 vs (0.676- vs 45.9% 345d 9999% 0.6085 (0.708- NAd 1.618) 157 improve- 1.223) ment) B_D PSMB9/ G/G Clinical AGEGRP <=65 Total 232 310 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R60H 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Protein CD68 0-50 Protein P27 % 0-70 Selected 156 230 289 N: % in 406d 125 (44.5% P- HR = NAd 0.4918 0.796 POSITIVE NUCLEI 66 ITT: vs improve- value = 0.655 vs (0.415- FOLLICULAR POSITIVE vs 23.1% 281d ment) 0.034 (0.44- NAd 1.527) 90 0.973) Protein CD68 0-50 Protein P27 % 0-70 Excluded 156 230 289 N: % in 367d 2 (0.49999- P- HR = NAd 0.6162 0.87 POSITIVE NUCLEI 124 ITT: vs 999999- value = 1.013 vs (0.505- FOLLICULAR POSITIVE vs 34.1% 365d 9989% 0.9376 (0.738- NAd 1.499) 106 improve- 1.39) ment) Protein CD68 0-50 Protein P27 % 0-70 Total 156 230 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE NUCLEI 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR POSITIVE vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB1/ C/G Clinical RACEGRP WHITE Selected 208 334 133 N: % in 444d 118 (36.2% P- HR = NAd 0.6910 0.889 NA P11A 97 ITT: vs improve- value = 0.714 vs (0.498- vs 30.8% 326d ment) 0.0499 (0.509- NAd 1.589) 111 1.001) B_D PSMB1/ C/G Clinical RACEGRP WHITE Excluded 208 334 133 N: % in 360d 15 (4.2999- P- HR = NAd 0.6309 1.109 NA P11A 169 ITT: vs 999999- value = 0.887 vs (0.726- vs 49.5% 345d 9999% 0.3716 (0.68- NAd 1.695) 165 improve- 1.155) ment) B_D PSMB1/ C/G Clinical RACEGRP WHITE Total 208 334 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical AGEGRP <=65 Protein P27 SIGNAL >=2+ Selected 302 161 212 N: % in 396d 117 (41.9% P- HR = NAd 0.4996 0.855 INTENSITY 149 ITT: vs improve- value = 0.742 vs (0.543- vs 44.7% 279d ment) 0.0348 (0.561- NAd 1.347) 153 0.98) Clinical AGEGRP <=65 Protein P27 SIGNAL >=2+ Excluded 302 161 212 N: % in 355d 6 (1.6999- P- HR = NAd 0.9211 0.968 INTENSITY 78 ITT: vs 999999- value = 1 vs (0.512- vs 23.9% 349d 9999% 0.9982 (0.691- NAd 1.831) 83 improve- 1.446) ment) Clinical AGEGRP <=65 Protein P27 SIGNAL >=2+ Total 302 161 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 INTENSITY 227 ITT: vs improve- value = 0.822 vs (0.62- vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Clinical SEX MALE Protein P27 % 0-70 Selected 120 343 212 N: % in 351d 116 (49.4% P- HR = NAd 0.2905 0.703 NUCLEI 64 ITT: vs improve- value = 0.639 vs (0.365- POSITIVE vs 17.8% 235d ment) 0.0331 (0.423- NAd 1.355) 56 0.967) Clinical SEX MALE Protein P27 % 0-70 Excluded 120 343 212 N: % in 380d 29 (8.3% P- HR = NAd 0.8108 0.947 NUCLEI 163 ITT: vs improve- value = 0.849 vs (0.605- POSITIVE vs 50.8% 351d ment) 0.2275 (0.651- NAd 1.482) 180 1.107) Clinical SEX MALE Protein P27 % 0-70 Total 120 343 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 NUCLEI 227 ITT: vs improve- value = 0.822 vs (0.62- POSITIVE vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Clinical AGEGRP <=65 Protein P65 >=2+ Selected 291 179 205 N: % in 396d 115 (40.9% P- HR = NAd 0.6033 0.883 INTENSITY 139 ITT: vs improve- value = 0.749 vs (0.551- CYTOPLASMIC vs 43.1% 281d ment) 0.0438 (0.564- NAd 1.413) SIGNAL 152 0.993) Clinical AGEGRP <=65 Protein P65 >=2+ Excluded 291 179 205 N: % in 360d 11 (3.2% P- HR = NAd 0.9236 0.971 INTENSITY 90 ITT: vs improve- value = 0.978 vs (0.534- CYTOPLASMIC vs 26.5% 349d ment) 0.9045 (0.685- NAd 1.767) SIGNAL 89 1.395) Clinical AGEGRP <=65 Protein P65 >=2+ Total 291 179 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 INTENSITY 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Protein CD68 0-50 Protein P65 % 0 Selected 208 178 289 N: % in 396d 114 (40.4% P- HR = NAd 0.3965 0.78 POSITIVE NUCLEAR 94 ITT: vs improve- value = 0.699 vs (0.439- FOLLICULAR STAINING vs 30.8% 282d ment) 0.0366 (0.499- NAd 1.387) 114 0.98) Protein CD68 0-50 Protein P65 % 0 Excluded 208 178 289 N: % in 406d 27 (7.1% P- HR = NAd 0.8015 0.925 POSITIVE NUCLEAR 96 ITT: vs improve- value = 1.094 vs (0.505- FOLLICULAR STAINING vs 26.4% 379d ment) 0.6341 (0.757- NAd 1.695) 82 1.581) Protein CD68 0-50 Protein P65 % 0 Total 208 178 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE NUCLEAR 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR STAINING vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Clinical FLIPI High Protein P65 >=2+ Selected 156 314 205 N: % in 352d 113 (47.3% P- HR = 1343d 0.5476 0.856 INTENSITY 76 ITT: vs improve- value = 0.653 vs (0.515- CYTOPLASMIC vs 23.1% 239d ment) 0.0229 (0.451- NAd 1.421) SIGNAL 80 0.945) Clinical FLIPI High Protein P65 >=2+ Excluded 156 314 205 N: % in 429d 81 (23.3% P- HR = NAd 0.9311 0.977 INTENSITY 153 ITT: vs improve- value = 0.919 vs (0.57- CYTOPLASMIC vs 46.5% 348d ment) 0.5476 (0.697- NAd 1.674) SIGNAL 161 1.211) Clinical FLIPI High Protein P65 >=2+ Total 156 314 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 INTENSITY 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) B_D PSMB1/ C/G Clinical HITUBD YES Selected 137 405 133 N: % in 351d 110 (45.6% P- HR = NAd 0.8487 0.942 NA P11A 65 ITT: vs improve- value = 0.643 vs (0.514- vs 20.3% 241d ment) 0.0273 (0.433- NAd 1.728) 72 0.955) B_D PSMB1/ C/G Clinical HITUBD YES Excluded 137 405 133 N: % in 429d 54 (14.4% P- HR = NAd 0.7275 1.076 NA P11A 201 ITT: vs improve- value= 0.893 vs (0.711- vs 60% 375d ment) 0.3654 (0.7- NAd 1.629) 204 1.14) B_D PSMB1/ C/G Clinical HITUBD YES Total 137 405 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Protein 20S >=3+ Protein CD68 0-50 Selected 138 248 289 N: % in 435d 109 (33.4% P- HR = NAd 0.1965 0.624 INTENSITY POSITIVE 66 ITT: vs improve- value = 0.657 vs (0.302- CYTOPLASMIC FOLLICULAR vs 20.4% 326d ment) 0.048 (0.432- NAd 1.285) SIGNAL 72 0.999) Protein 20S >=3+ Protein CD68 0-50 Excluded 138 248 289 N: % in 352d 4 (1.0999- P- HR = NAd 0.9537 0.985 INTENSITY POSITIVE 124 ITT: vs 999999- value = 0.976 vs (0.591- CYTOPLASMIC FOLLICULAR vs 36.7% 348d 9999% 0.8748 (0.721- NAd 1.641) SIGNAL 124 improve- 1.322) ment) Protein 20S >=3+ Protein CD68 0-50 Total 138 248 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 INTENSITY POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- CYTOPLASMIC FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) SIGNAL 196 1.08) Clinical FLIPI High Protein P27 SIGNAL >=2+ Selected 164 299 212 N: % in 346d 107 (44.8% P- HR = 1343d 0.2893 0.761 INTENSITY 81 ITT: vs improve- value = 0.694 vs (0.459- vs 24.3% 239d ment) 0.0449 (0.485- 1263d 1.262) 83 0.993) Clinical FLIPI High Protein P27 SIGNAL >=2+ Excluded 164 299 212 N: % in 429d 72 (20.2% P- HR = NAd 0.8014 1.072 INTENSITY 146 ITT: vs improve- value = 0.883 vs (0.622- vs 44.3% 357d ment) 0.3899 (0.665- NAd 1.848) 153 1.173) Clinical FLIPI High Protein P27 SIGNAL >=2+ Total 164 299 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 INTENSITY 227 ITT: vs improve- value = 0.822 vs (0.62- vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Clinical PRITUX NO Protein P65 % >90% Selected 217 253 205 N: % in 426d 104 (32.3% P- HR = NAd 0.2559 0.732 POSITIVE 105 ITT: vs improve- value = 0.677 vs (0.427- CYTOPLASMIC vs 32.1% 322d ment) 0.0193 (0.488- NAd 1.256) SIGNAL 112 0.94) Clinical PRITUX NO Protein P65 % >90% Excluded 217 253 205 N: % in 345d −1 (−0.3% P- HR = NAd 0.5660 1.161 POSITIVE 124 ITT: vs improve- value = 0.987 vs (0.697- CYTOPLASMIC vs 37.5% 346d ment) 0.9336 (0.731- NAd 1.936) SIGNAL 129 1.333) Clinical PRITUX NO Protein P65 % >90% Total 217 253 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) B_D PSMB1/ C/G Protein P65 >=2+ Selected 154 283 238 N: % in 426d 104 (32.3% P- HR = NAd 0.3233 0.71 NA P11A INTENSITY 73 ITT: vs improve- value = 0.645 vs (0.358- CYTOPLASMIC vs 22.8% 322d ment) 0.027 (0.435- NAd 1.406) SIGNAL 81 0.955) B_D PSMB1/ C/G Protein P65 >=2+ Excluded 154 283 238 N: % in 360d 14 (4% P- HR = NAd 0.8398 1.049 NA P11A INTENSITY 140 ITT: vs improve- value = 0.86 vs (0.66- CYTOPLASMIC vs 41.9% 346d ment) 0.2961 (0.648- NAd 1.666) SIGNAL 143 1.141) B_D PSMB1/ C/G Protein P65 >=2+ Total 154 283 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA P11A INTENSITY 213 ITT: vs improve- value = 0.782 vs (0.634- CYTOPLASMIC vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) SIGNAL 224 0.984) B_D PSMB1/ C/G Clinical PRITUX NO Selected 138 404 133 N: % in 426d 104 (32.3% P- HR = NAd 0.4750 0.786 NA P11A 70 ITT: vs improve- value = 0.658 vs (0.404- vs 20.4% 322d ment) 0.0388 (0.44- NAd 1.528) 68 0.982) B_D PSMB1/ C/G Clinical PRITUX NO Excluded 138 404 133 N: % in 363d 18 (5.2% P- HR = NAd 0.5551 1.127 NA P11A 196 ITT: vs improve- value = 0.898 vs (0.757- vs 59.9% 345d ment) 0.3874 (0.705- NAd 1.68) 208 1.145) B_D PSMB1/ C/G Clinical PRITUX NO Total 138 404 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA P11A 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) B_D PSMB9/ G/G Protein CD68 0-50 Selected 145 211 319 N: % in 429d 103 (31.6% P- HR = NAd 0.1089 0.565 NA R60H POSITIVE 66 ITT: vs improve- value = 0.641 vs (0.279- FOLLICULAR vs 21.5% 326d ment) 0.0269 (0.43- NAd 1.146) 79 0.954) B_D PSMB9/ G/G Protein CD68 0-50 Excluded 145 211 319 N: % in 406d 59 (17% P- HR = NAd 0.9946 0.998 NA R60H POSITIVE 109 ITT: vs improve- value = 0.947 vs (0.576- FOLLICULAR vs 31.3% 347d ment) 0.7477 (0.677- NAd 1.731) 102 1.324) B_D PSMB9/ G/G Protein CD68 0-50 Total 145 211 319 N: % in 414d 69 (20% P- HR = NAd 0.3270 0.808 NA R60H POSITIVE 175 ITT: vs improve- value = 0.801 vs (0.527- FOLLICULAR vs 52.7% 345d ment) 0.0855 (0.621- NAd 1.239) 181 1.032) Protein 20S >=3+ Protein P65 % >90% Selected 195 268 212 N: % in 435d 101 (30.2% P- HR = NAd 0.1802 0.66 INTENSITY POSITIVE 95 ITT: vs improve- value = 0.681 vs (0.358- CYTOPLASMIC CYTOPLASMIC vs 28.9% 334d ment) 0.0304 (0.481- NAd 1.217) SIGNAL SIGNAL 100 0.965) Protein 20S >=3+ Protein P65 % >90% Excluded 195 268 212 N: % in 351d 6 (1.6999- P- HR = NAd 0.5860 1.141 INTENSITY POSITIVE 130 ITT: vs 999999- value = 0.959 vs (0.709- CYTOPLASMIC CYTOPLASMIC vs 39.7% 345d 9999% 0.7745 (0.718- NAd 1.838) SIGNAL SIGNAL 138 improve- 1.28) ment) Protein 20S >=3+ Protein P65 % >90% Total 195 268 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 INTENSITY POSITIVE 225 ITT: vs improve- value = 0.83 vs (0.634- CYTOPLASMIC CYTOPLASMIC vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) SIGNAL SIGNAL 238 1.037) Clinical RACEGRP WHITE Protein CD68 0-50 Selected 239 147 289 N: % in 431d 97 (29% P- HR = NAd 0.0785 0.592 POSITIVE 114 ITT: vs improve- value = 0.63 vs (0.328- FOLLICULAR vs 35.4% 334d ment) 0.0043 (0.458- NAd 1.069) 125 0.868) Clinical RACEGRP WHITE Protein CD68 0-50 Excluded 239 147 289 N: % in 324d −51 (−13.6% P- HR = NAd 0.5253 1.215 POSITIVE 76 ITT: vs improve- value = 1.294 vs (0.665- FOLLICULAR vs 21.8% 375d ment) 0.1919 (0.878- NAd 2.219) 71 1.908) Clinical RACEGRP WHITE Protein CD68 0-50 Total 239 147 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Protein 20S % 30-90 Protein CD68 0-50 Selected 168 271 236 N: % in 367d 96 (35.4% P- HR = NAd 0.3345 0.753 NUCLEAR OVERALL 82 ITT: vs improve- value = 0.647 vs (0.424- STAINING POSITIVE vs 24.9% 271d ment) 0.0181 (0.45- NAd 1.34) 86 0.931) Protein 20S % 30-90 Protein CD68 0-50 Excluded 168 271 236 N: % in 355d −10 (−2.7% P- HR = NAd 0.8394 1.055 NUCLEAR OVERALL 134 ITT: vs improve- value = 0.949 vs (0.627- STAINING POSITIVE vs 40.1% 365d ment) 0.7301 (0.706- NAd 1.774) 137 1.276) Protein 20S % 30-90 Protein CD68 0-50 Total 168 271 236 N: % in 366d 21 (6.1% P- HR = NAd 0.6244 0.908 NUCLEAR OVERALL 216 ITT: vs improve- value = 0.818 vs (0.618- STAINING POSITIVE vs 65% 345d ment) 0.0853 (0.651- NAd 1.335) 223 1.029) Clinical AGEGRP <=65 Protein 20S % 30-90 Selected 193 270 212 N: % in 367d 96 (35.4% P- HR = NAd 0.6180 0.865 NUCLEAR 96 ITT: vs improve- value = 0.703 vs (0.49- STAINING vs 28.6% 271d ment) 0.0413 (0.5- NAd 1.527) 97 0.988) Clinical AGEGRP <=65 Protein 20S % 30-90 Excluded 193 270 212 N: % in 380d 23 (6.4% P- HR = NAd 0.8251 0.946 NUCLEAR 129 ITT: vs improve- valne = 0.925 vs (0.576- STAINING vs 40% 357d ment) 0.6011 (0.689- NAd 1.552) 141 1.241) Clinical AGEGRP <=65 Protein 20S % 30-90 Total 193 270 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) 238 1.037) Clinical HITUBD YES Protein P65 % >90% Selected 202 268 205 N: % in 346d 93 (36.8% P- HR = 1343d 0.7230 0.917 POSITIVE 100 ITT: vs improve- value = 0.728 vs (0.567- CYTOPLASMIC vs 29.9% 253d ment) 0.0486 (0.531- NAd 1.481) SIGNAL 102 0.999) Clinical HITUBD YES Protein P65 % >90% Excluded 202 268 205 N: % in 487d 65 (15.4% P- HR = NAd 0.6827 0.886 POSITIVE 129 ITT: vs improve- value = 0.88 vs (0.496- CYTOPLASMIC vs 39.7% 422d ment) 0.4198 (0.646- NAd 1.584) SIGNAL 139 1.199) Clinical HITUBD YES Protein P65 % >90% Total 202 268 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Protein 20S % 30-90 Protein CD68 0-50 Selected 164 222 289 N: % in 366d 92 (33.6% P- HR = NAd 0.2666 0.702 NUCLEAR POSITIVE 75 ITT: vs improve- value = 0.631 vs (0.374- STAINING FOLLICULAR vs 24.3% 274d ment) 0.0133 (0.437- NAd 1.315) 89 0.911) Protein 20S % 30-90 Protein CD68 0-50 Excluded 164 222 289 N: % in 422d −5 (−1.2% P- HR = NAd 0.9562 0.984 NUCLEAR POSITIVE 115 ITT: vs improve- value = 1.072 vs (0.561- STAINING FOLLICULAR vs 32.9% 427d ment) 0.6841 (0.769- NAd 1.727) 107 1.494) Protein 20S % 30-90 Protein CD68 0-50 Total 164 222 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 NUCLEAR POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- STAINING FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB5/ C/C Clinical AGEGRP <=65 Selected 337 205 133 N: % in 422d 92 (27.9% P- HR = NAd 0.9869 1.004 NA R24C 167 ITT: vs improve- value = 0.722 vs (0.638- vs 49.9% 330d ment) 0.0146 (0.555- NAd 1.579) 170 0.939) B_D PSMB5/ C/C Clinical AGEGRP <=65 Excluded 337 205 133 N: % in 355d 7 (2% P- HR = NAd 0.7965 1.071 NA R24C 99 ITT: vs improve- value = 1.037 vs (0.636- vs 30.4% 348d ment) 0.8278 (0.739- NAd 1.801) 106 1.457) B_D PSMB5/ C/C Clinical AGEGRP <=65 Total 337 205 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R24C 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) B_D PSMB5/ C/C Protein CD68 0-50 Selected 225 131 319 N: % in 426d 92 (27.5% P- HR = NAd 0.2817 0.729 NA R24C POSITIVE 104 ITT: vs improve- value = 0.691 vs (0.41- FOLLICULAR vs 33.3% 334d ment) 0.0247 (0.499- NAd 1.298) 121 0.956) B_D PSMB5/ C/C Protein CD68 0-50 Excluded 225 131 319 N: % in 414d 66 (19% P- HR = NAd 0.7179 0.888 NA R24C POSITIVE 71 ITT: vs improve- value = 1.046 vs (0.466- FOLLICULAR vs 19.4% 348d ment) 0.8308 (0.687- NAd 1.692) 60 1.594) B_D PSMB5/ C/C Protein CD68 0-50 Total 225 131 319 N: % in 414d 69 (20% P- HR = NAd 0.3270 0.808 NA R24C POSITIVE 175 ITT: vs improve- value = 0.801 vs (0.527- FOLLICULAR vs 52.7% 345d ment) 0.0855 (0.621- NAd 1.239) 181 1.032) Clinical SEX FEMALE Protein CD68 0-50 Selected 163 223 239 N: % in 435d 90 (26.1% P- HR = NAd 0.5324 0.794 POSITIVE 69 ITT: vs improve- value = 0.609 vs (0.385- FOLLICULAR vs 24.1% 345d ment) 0.015 (0.406- NAd 1.639) 94 0.913) Clinical SEX FEMALE Protein CD68 0-50 Excluded 163 223 239 N: % in 352d 5 (1.4% P- HR = NAd 0.4476 0.821 POSITIVE 121 ITT: vs improve- value = 1.031 vs (0.493- FOLLICULAR vs 33% 347d ment) 0.854 (0.75- NAd 1.368) 102 1.416) Clinical SEX FEMALE Protein CD68 0-50 Total 163 223 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB9/ A/G Protein P65 % 0 Selected 120 317 238 N: % in 366d 89 (32.1% P- HR = NAd 0.2104 0.635 NA R60H NUCLEAR 60 ITT: vs improve- value = 0.6 vs (0.31- STAINING vs 17.8% 277d ment) 0.0212 (0.386- NAd 1.3) 60 0.93) B_D PSMB9/ A/G Protein P65 % 0 Excluded 120 317 238 N: % in 415d 67 (19.3% P- HR = NAd 0.7295 1.083 NA R60H NUCLEAR 153 ITT: vs improve- value = 0.851 vs (0.689- STAINING vs 47% 348d ment) 0.2428 (0.65- NAd 1.704) 164 1.115) B_D PSMB9/ A/G Protein P65 % 0 Total 120 317 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA R60H NUCLEAR 213 ITT: vs improve- value = 0.782 vs (0.634- STAINING vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) 224 0.984) Protein 20S % 95-100 Protein CD68 0-50 Selected 183 203 289 N: % in 426d 88 (26% P- HR = NAd 0.0772 0.578 POSITIVE POSITIVE 90 ITT: vs improve- value = 0.646 vs (0.313- CYTOPLASMIC FOLLICULAR vs 27.1% 338d ment) 0.0168 (0.449- NAd 1.069) SIGNAL 93 0.928) Protein 20S % 95-100 Protein CD68 0-50 Excluded 183 203 289 N: % in 351d 4 (1.2% P- HR = NAd 0.5747 1.178 POSITIVE POSITIVE 100 ITT: vs improve- value = 1.066 vs (0.664- CYTOPLASMIC FOLLICULAR vs 30.1% 347d ment) 0.7086 (0.762- NAd 2.09) SIGNAL 103 1.49) Protein 20S % 95-100 Protein CD68 0-50 Total 183 203 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- CYTOPLASMIC FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) SIGNAL 196 1.08) B_D PSMB5/ C/C Protein P65 % >90% Selected 300 137 238 N: % in 422d 88 (26.3% P- HR = NAd 0.6127 0.887 NA R24C POSITIVE 141 ITT: vs improve- value = 0.713 vs (0.558- CYTOPLASMIC vs 44.4% 334d ment) 0.017 (0.54- NAd 1.411) SIGNAL 159 0.943) B_D PSMB5/ C/C Protein P65 % >90% Excluded 300 137 238 N: % in 352d 5 (1.4% P- HR = NAd 0.9886 1.005 NA R24C POSITIVE 72 ITT: vs improve- value = 0.953 vs (0.513- CYTOPLASMIC vs 20.3% 347d ment) 0.819 (0.633- NAd 1.972) SIGNAL 65 1.435) B_D PSMB5/ C/C Protein P65 % >90% Total 300 137 238 N: % in 414d 76 (22.5% P- HR = NAd 0.7048 0.929 NA R24C POSITIVE 213 ITT: vs improve- value = 0.782 vs (0.634- CYTOPLASMIC vs 64.7% 338d ment) 0.0354 (0.622- NAd 1.36) SIGNAL 224 0.984) Protein P27 >=2+ Protein P65 % >90% Selected 348 114 213 N: % in 414d 88 (27% P- HR = NAd 0.2119 0.76 SIGNAL POSITIVE 168 ITT: vs improve- value = 0.755 vs (0.493- INTENSITY CYTOPLASMIC vs 51.6% 326d ment) 0.0333 (0.583- NAd 1.171) SIGNAL 180 0.979) Protein P27 >=2+ Protein P65 % >90% Excluded 348 114 213 N: % in 347d 0 (0% P- HR = NAd 0.3256 1.455 SIGNAL POSITIVE 58 ITT: vs improve- value = 1.04 vs (0.686- INTENSITY CYTOPLASMIC vs 16.9% 347d ment) 0.8643 (0.669- NAd 3.086) SIGNAL 56 1.617) Protein P27 >=2+ Protein P65 % >90% Total 348 114 213 N: % in 366d 21 (6.1% P- HR = NAd 0.5839 0.902 SIGNAL POSITIVE 226 ITT: vs improve- value = 0.817 vs (0.623- INTENSITY CYTOPLASMIC vs 68.4% 345d ment) 0.0753 (0.654- NAd 1.305) SIGNAL 236 1.021) Clinical HITUBD YES Protein P27 % 0-70 Selected 148 315 212 N: % in 324d 85 (35.6% P- HR = 1343d 0.7672 0.918 NUCLEI 75 ITT: vs improve- value = 0.677 vs (0.524- POSITIVE vs 21.9% 239d ment) 0.0384 (0.466- NAd 1.61) 73 0.982) Clinical HITUBD YES Protein P27 % 0-70 Excluded 148 315 212 N: % in 426d 69 (19.3% P- HR = NAd 0.4225 0.817 NUCLEI 152 ITT: vs improve- value = 0.852 vs (0.498- POSITIVE vs 46.7% 357d ment) 0.2588 (0.645- NAd 1.34) 163 1.126) Clinical HITUBD YES Protein P27 % 0-70 Total 148 315 212 N: % in 366d 21 (6.1% P- HR = NAd 0.5615 0.896 NUCLEI 227 ITT: vs improve- value = 0.822 vs (0.62- POSITIVE vs 68.6% 345d ment) 0.0844 (0.659- NAd 1.297) 236 1.027) Clinical RACEGRP WHITE Protein P65 % >90% Selected 341 129 205 N: % in 417d 83 (24.9% P- HR = NAd 0.2846 0.783 POSITIVE 162 ITT: vs improve- value = 0.725 vs (0.501- CYTOPLASMIC vs 50.5% 334d ment) 0.0163 (0.558- NAd 1.226) SIGNAL 179 0.943) Clinical RACEGRP WHITE Protein P65 % >90% Excluded 341 129 205 N: % in 346d −32 (−8.5% P- HR = NAd 0.5035 1.257 POSITIVE 67 ITT: vs improve- value = 1.159 vs (0.643- CYTOPLASMIC vs 19.1% 378d ment) 0.4834 (0.767- NAd 2.455) SIGNAL 62 1.752) Clinical RACEGRP WHITE Protein P65 % >90% Total 341 129 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Clinical ANNARBOR >=III Protein P65 % >90% Selected 321 149 205 N: % in 360d 82 (29.5% P- HR = NAd 0.5983 0.891 POSITIVE 152 ITT: vs improve- value = 0.75 vs (0.58- CYTOPLASMIC vs 47.6% 278d ment) 0.0306 (0.578- NAd 1.369) SIGNAL 169 0.974) Clinical ANNARBOR >=III Protein P65 % >90% Excluded 321 149 205 N: % in 435d 3 (0.6999- P- HR = NAd 0.8428 1.077 POSITIVE 77 ITT: vs 999999- value = 1.063 vs (0.518- CYTOPLASMIC vs 22.1% 432d 9999% 0.78 (0.696- NAd 2.242) SIGNAL 72 improve- 1.622) ment) Clinical ANNARBOR >=III Protein P65 % >90% Total 321 149 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) Clinical REGION REST Protein CD68 0-50 Selected 137 304 234 N: % in 358d 81 (29.2% P- HR = NAd 0.2957 0.716 OF OVERALL 67 ITT: vs improve- value = 0.668 vs (0.382- WORLD POSITIVE vs 20.3% 277d ment) 0.0407 (0.452- NAd 1.341) 70 0.987) Clinical REGION REST Protein CD68 0-50 Excluded 137 304 234 N: % in 380d 29 (8.3% P- HR = NAd 0.9650 1.011 OF OVERALL 150 ITT: vs improve- value = 0.917 vs (0.621- WORLD POSITIVE vs 45% 351d ment) 0.552 (0.691- NAd 1.645) 154 1.217) Clinical REGION REST Protein CD68 0-50 Total 137 304 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OF OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- WORLD POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) Clinical RACEGRP WHITE Protein CD68 0-50 Selected 260 181 234 N: % in 414d 80 (24% P- HR = NAd 0.1697 0.701 OVERALL 132 ITT: vs improve- value = 0.71 vs (0.421- POSITIVE vs 38.5% 334d ment) 0.0248 (0.526- NAd 1.167) 128 0.959) Clinical RACEGRP WHITE Protein CD68 0-50 Excluded 260 181 234 N: % in 351d 3 (0.8999- P- HR = NAd 0.4069 1.28 OVERALL 85 ITT: vs 999999- value = 0.991 vs (0.713- POSITIVE vs 26.8% 348d 9999% 0.9662 (0.696- NAd 2.299) 96 improve- 1.411) ment) Clinical RACEGRP WHITE Protein CD68 0-50 Total 260 181 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) Clinical FLIPI High Protein CD68 0-50 Selected 135 306 234 N: % in 352d 79 (28.9% P- HR = 1343d 0.2526 0.727 OVERALL 67 ITT: vs improve- value = 0.658 vs (0.421- POSITIVE vs 20% 273d ment) 0.0339 (0.446- NAd 1.257) 68 0.971) Clinical FLIPI High Protein CD68 0-50 Excluded 135 306 234 N: % in 414d 57 (16% P- HR = NAd 0.9548 0.984 OVERALL 150 ITT: vs improve- value = 0.898 vs (0.574- POSITIVE vs 45.3% 357d ment) 0.4519 (0.677- NAd 1.687) 156 1.191) Clinical FLIPI High Protein CD68 0-50 Total 135 306 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) B_D PSMB5/ C/C Clinical ANNARBOR >=III Selected 375 167 133 N: % in 360d 79 (28.1% P- HR = NAd 0.5509 1.127 NA R24C 182 ITT: vs improve- value = 0.776 vs (0.761- vs 55.6% 281d ment) 0.0395 (0.61- NAd 1.668) 193 0.989) B_D PSMB5/ C/C Clinical ANNARBOR >=III Excluded 375 167 133 N: % in 512d 90 (21.3% P- HR = NAd 0.5602 0.814 NA R24C 84 ITT: vs improve- value = 0.996 vs (0.406- vs 24.7% 422d ment) 0.9843 (0.662- NAd 1.631) 83 1.499) B_D PSMB5/ C/C Clinical ANNARBOR >=III Total 375 167 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R24C 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) B_D PSMB5/ C/T Clinical HITUBD YES Selected 45 497 133 N: % in 352d 77 (28% P- HR = NAd 0.1763 0.496 NA R24C 24 ITT: vs improve- value = 0.383 vs (0.176- vs 6.7% 275d ment) 0.0054 (0.191- NAd 1.399) 21 0.769) B_D PSMB5/ C/T Clinical HITUBD YES Excluded 45 497 133 N: % in 414d 67 (19.3% P- HR = NAd 0.5518 1.116 NA R24C 242 ITT: vs improve- value = 0.856 vs (0.777- vs 73.6% 347d ment) 0.1634 (0.688- NAd 1.605) 255 1.065) B_D PSMB5/ C/T Clinical HITUBD YES Total 45 497 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R24C 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Protein CD68 0-50 Protein P27 % 0-70 Selected 181 260 234 N: % in 358d 76 (27% P- HR = NAd 0.5757 0.851 OVERALL NUCLEI 85 ITT: vs improve- value = 0.699 vs (0.485- POSITIVE POSITIVE vs 26.8% 282d ment) 0.0484 (0.488- NAd 1.496) 96 1) Protein CD68 0-50 Protein P27 % 0-70 Excluded 181 260 234 N: % in 367d 18 (5.2% P- HR = NAd 0.7267 0.911 OVERALL NUCLEI 132 ITT: vs improve- value = 0.901 vs (0.539- POSITIVE POSITIVE vs 38.5% 349d ment) 0.4931 (0.669- NAd 1.538) 128 1.213) Protein CD68 0-50 Protein P27 % 0-70 Total 181 260 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL NUCLEI 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE POSITIVE vs 65.3 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) B_D PSMB9/ A/G Clinical SEX MALE Selected 76 466 133 N: % in 348d 75 (27.5% P- HR = NAd 0.7868 0.879 NA R60H 48 ITT: vs improve- value = 0.583 vs (0.345- vs 11.3% 273d ment) 0.0491 (0.337- NAd 2.242) 28 1.008) B_D PSMB9/ A/G Clinical SEX MALE Excluded 76 466 133 N: % in 422d 74 (21.3% P- HR = NAd 0.7578 1.06 NA R60H 218 ITT: vs improve- value = 0.835 vs (0.733- vs 69% 348d ment) 0.1201 (0.666- NAd 1.533) 248 1.048) B_D PSMB9/ A/G Clinical SEX MALE Total 76 466 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R60H 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Protein CD68 0-50 Protein P27 >=2+ Selected 252 189 234 N: % in 396d 74 (23% P- HR = NAd 0.1214 0.676 OVERALL SIGNAL 129 ITT: vs improve- value = 0.734 vs (0.411- POSITIVE INTENSITY vs 37.3% 322d ment) 0.0434 (0.543- NAd 1.113) 231 0.992) Protein CD68 0-50 Protein P27 >=2+ Excluded 252 189 234 N: % in 352d 4 (1.0999 P- HR = NAd 0.3802 1.31 OVERALL SIGNAL 88 ITT: vs 999999 value = 0.944 vs (0.715- POSITIVE INTENSITY vs 28% 348d 9999% 0.7527 (0.665- NAd 2.402) 101 improve- 1.34) ment) Protein CD68 0-50 Protein P27 >=2+ Total 252 189 234 N: % in 360d 15 (4.2999- P- HR = NAd 0.5387 0.887 OVERALL SIGNAL 217 ITT: vs 999999- value = 0.819 vs (0.604- POSITIVE INTENSITY vs 65.3% 345d 9999% 0.0864 (0.652- NAd 1.301) 224 improve- 1.029) ment) Clinical ANNARBOR >=III Protein CD68 0-50 Selected 239 147 289 N: % in 351d 73 (26.3% P- HR = NAd 0.2011 0.71 POSITIVE 110 ITT: vs improve- value = 0.693 vs (0.419- FOLLICULAR vs 35.4% 278d ment) 0.0172 (0.512- NAd 1.203) 129 0.939) Clinical ANNARBOR >=III Protein CD68 0-50 Excluded 239 147 289 N: % in 435d −57 (−11.6% P- HR = NAd 0.6331 1.187 POSITIVE 80 ITT: vs improve- value = 1.29 vs (0.586- FOLLICULAR vs 21.8% 492d ment) 0.248 (0.837- NAd 2.406) 67 1.989) Clinical ANNARBOR >=III Protein CD68 0-50 Total 239 147 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Clinical FLIPI Inter- Protein P65 % <=90% Selected 35 435 205 N: % in 351d −216 (−38.1% P- HR = NAd 0.6255 1.524 mediate POSITIVE 19 ITT: vs improve- value = 2.941 vs (0.277- CYTOPLASMIC vs 5.2% 567d ment) 0.0277 (1.075- NAd 8.379) SIGNAL 16 8.05) Clinical FLIPI Inter- Protein P65 % <=90% Excluded 35 435 205 N: % in 396d 70 (21.5% P- HR = NAd 0.5888 0.9 mediate POSITIVE 210 ITT: vs improve- value = 0.761 vs (0.616- CYTOPLASMIC vs 64.4% 326d ment) 0.0193 (0.605- NAd 1.317) SIGNAL 225 0.957) Clinical FLIPI Inter- Protein P65 % <=90% Total 35 435 205 N: % in 367d 22 (6.4% P- HR = NAd 0.6612 0.921 mediate POSITIVE 229 ITT: vs improve- value = 0.826 vs (0.636- CYTOPLASMIC vs 69.6% 345d ment) 0.0902 (0.663- NAd 1.332) SIGNAL 241 1.03) B_D PSMB9/ A/A Clinical ANNARBOR <=II Selected 10 532 133 N: % in 87d −260 (−74.9% P- HR = 140d 0.0009 8342757- NA R60H 2 ITT: vs improve- value = 12.341 vs 52.139 vs 1.5% 347d ment) 0.01 (1.094- NAd (0-Inf) 8 139.179) B_D PSMB9/ A/A Clinical ANNARBOR <=II Excluded 10 532 133 N: % in 414d 80 (24% P- HR = NAd 0.9481 0.989 NA R60H 264 ITT: vs improve- value = 0.814 vs (0.7- vs 78.8% 334d ment) 0.0538 (0.66- NAd 1.396) 268 1.004) B_D PSMB9/ A/A Clinical ANNARBOR <=II Total 10 532 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R60H 266 ITT: vs improve- value = 0.828 vs (0.734- vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) Clinical AGEGRP >65 Protein CD68 >50 Selected 25 361 239 N: % in 324d −384 (−54.2% P- HR = NAd 0.8613 0.895 POSITIVE 13 ITT: vs improve- value = 2.999 vs (0.257- FOLLICULAR vs 3.7% 708d ment) 0.0252 (1.095- 971d 3.112) 12 8.21) Clinical AGEGRP >65 Protein CD68 >50 Excluded 25 361 289 N: % in 414d 76 (22.5% P- HR = NAd 0.4138 0.833 POSITIVE 177 ITT: vs improve- value = 0.784 vs (0.536- FOLLICULAR vs 53.5% 338d ment) 0.0595 (0.608- NAd 1.293) 184 1.011) Clinical AGEGRP >65 Protein CD68 >50 Total 25 361 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Clinical RACEGRP OTHER Protein 20S % 0-20 Selected 7 456 212 N: % in 351d −412 (−54% P- HR = 371d 0.1573 281008- NUCLEAR 2 ITT: vs improve- value = 1861675- vs 16.562 STAINING vs 1% 763d ment) 0.0455 64.897 NAd (0-Inf) 5 (0-Inf) Clinical RACEGRP OTHER Protein 20S % 0-20 Excluded 7 456 212 N: % in 367d 29 (8.6% P- HR = NAd 0.5543 0.893 NUCLEAR 223 ITT: vs improve- value = 0.815 vs (0.614- STAINING vs 67.6% 338d ment) 0.072 (0.652- NAd 1.299) 233 1.019) Clinical RACEGRP OTHER Protein 20S % 0-20 Total 7 456 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 NUCLEAR 225 ITT: vs improve- value = 0.83 vs (0.634- STAINING vs 68.6% 343d ment) 0.1 (0.665- NAd 1.336) 238 1.037) Protein 20S >=3+ Protein P65 % <=90% Selected 18 445 212 N: % in 191d −517 (−73% P- HR = NAd 0.3995 0.525 INTENSITY POSITIVE 12 ITT: vs improve- value = 9.726 vs (0.114- CYTOPLASMIC CYTOPLASMIC vs 2.7% 708d ment) 0.0111 (1.204- 717d 2.411) SIGNAL SIGNAL 6 78.546) Protein 20S >=3+ Protein P65 % <=90% Excluded 18 445 212 N: % in 396d 58 (17.2% P- HR = NAd 0.7212 0.932 INTENSITY POSITIVE 213 ITT: vs improve- value = 0.781 vs (0.634- CYTOPLASMIC CYTOPLASMIC vs 65.9% 338d ment) 0.033 (0.622- NAd 1.37) SIGNAL SIGNAL 232 0.981) Protein 20S >=3+ Protein P65 % <=90% Total 18 445 212 N: % in 367d 22 (6.4% P- HR = NAd 0.6640 0.921 INTENSITY POSITIVE 225 ITT: vs improve- value = 0.83 vs (0.634- CYTOPLASMIC CYTOPLASMIC vs 68.6% 345d ment) 0.1 (0.665- NAd 1.336) SIGNAL SIGNAL 238 1.037) Clinical SEX FEMALE Protein CD68 >50 Selected 54 332 289 N: % in 344d −545 (−61.3% P- HR = 1078d 0.0178 3.398 POSITIVE 22 ITT: vs improve- value = 2.293 vs (1.16- FOLLICULAR vs 8% 889d ment) 0.0156 (1.149- NAd 9.958) 32 4.575) Clinical SEX FEMALE Protein CD68 >50 Excluded 54 332 289 N: % in 414d 131 (46.3% P- HR = NAd 0.0624 0.649 POSITIVE 168 ITT: vs improve- value = 0.698 vs (0.41- FOLLICULAR vs 49.2% 283d ment) 0.007 (0.537- NAd 1.026) 164 0.908) Clinical SEX FEMALE Protein CD68 >50 Total 54 332 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) Protein CD68 >50 Protein P65 % <=90% Selected 8 378 289 N: % in 487d −596 (−55% P- HR = NAd 0.1967 0 POSITIVE POSITIVE 5 ITT: vs improve- value = 1558276- vs (0-Inf) FOLLICULAR CYTOPLASMIC vs 1.2% 1083d ment) 0.0136 6.206 NAd SIGNAL 3 (0-Inf) Protein CD68 >50 Protein P65 % <=90% Excluded 8 378 289 N: % in 396d 51 (14.8% P- HR = NAd 0.5254 0.874 POSITIVE POSITIVE 185 ITT: vs improve- value = 0.821 vs (0.576- FOLLICULAR CYTOPLASMIC vs 56% 345d ment) 0.1162 (0.641- NAd 1.325) SIGNAL 193 1.051) Protein CD68 >50 Protein P65 % <=90% Total 8 378 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 POSITIVE POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- FOLLICULAR CYTOPLASMIC vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) SIGNAL 196 1.08) Protein CD68 >50 Protein P65 % <=90% Selected 8 432 235 N: % in 144d −607 (−80.8% P- HR = 887d 0.1970 704857- OVERALL POSITIVE 5 ITT: vs improve- value = 1217047- vs 1.582 POSITIVE CYTOPLASMIC vs 1.2% 751d ment) 0.0434 1.716 NAd (0-Inf) SIGNAL 3 (0-Inf) Protein CD68 >50 Protein P65 % <=90% Excluded 8 432 235 N: % in 380d 35 (10.1% P- HR = NAd 0.3832 0.841 OVERALL POSITIVE 211 ITT: vs improve- value = 0.793 vs (0.57- POSITIVE CYTOPLASMIC vs 64% 345d ment) 0.0487 (0.63- NAd 1.242) SIGNAL 221 0.999) Protein CD68 >50 Protein P65 % <=90% Total 8 432 235 N: % in 366d 21 (6.1% P- HR = NAd 0.5608 0.892 OVERALL POSITIVE 216 ITT: vs improve- value = 0.814 vs (0.608- POSITIVE CYTOPLASMIC vs 65.2% 345d ment) 0.0769 (0.648- NAd 1.309) SIGNAL 224 1.023) Protein CD68 >50 Protein CD68 0-50 Selected 45 339 291 N: % in 344d −739 (−68.2% P- HR = NAd 0.3295 1.784 POSITIVE POSITIVE 26 ITT: vs improve- value = 2.642 vs (0.548- FOLLICULAR PERI- vs 6.7% 1083d ment) 0.0143 (1.182- NAd 5.8) FOLLICULAR 19 5.908) Protein CD68 >50 Protein CD68 0-50 Excluded 45 339 291 N: % in 414d 88 (27% P- HR = NAd 0.1951 0.743 POSITIVE POSITIVE 163 ITT: vs improve- value = 0.739 vs (0.473- FOLLICULAR PERI- vs 50.2% 326d ment) 0.0227 (0.569- NAd 1.167) FOLLICULAR 176 0.96) Protein CD68 >50 Protein CD68 0-50 Total 45 339 291 N: % in 406d 60 (17.3% P- HR = NAd 0.4116 0.841 POSITIVE POSITIVE 189 ITT: vs improve- value = 0.845 vs (0.555- FOLLICULAR PERI- vs 56.9% 346d ment) 0.1772 (0.662- NAd 1.273) FOLLICULAR 195 1.08) Protein CD68 0-50 Protein CD68 >50 Selected 32 354 289 N: % in 307d NA (NA% P- HR = NAd 0.4981 1.592 OVERALL POSITIVE 19 ITT: vs improve- value = 3.155 vs (0.41- POSITIVE FOLLICULAR vs 4.7% NAd ment) 0.0127 (1.22- NAd 6.178) 13 8.164) Protein CD68 0-50 Protein CD68 >50 Excluded 32 354 289 N: % in 406d 80 (24.5% P- HR = NAd 0.2670 0.779 OVERALL POSITIVE 171 ITT: vs improve- value = 0.755 vs (0.501- POSITIVE FOLLICULAR vs 52.4% 326d ment) 0.0309 (0.585- NAd 1.212) 183 0.976) Protein CD68 0-50 Protein CD68 >50 Total 32 354 289 N: % in 396d 50 (14.5% P- HR = NAd 0.4068 0.839 OVERALL POSITIVE 190 ITT: vs improve- value = 0.846 vs (0.554- POSITIVE FOLLICULAR vs 57.2% 346d ment) 0.1781 (0.663- NAd 1.27) 196 1.08) B_D PSMB9/ A/A Clinical REGION UNITED Selected 6 536 133 N: % in 75d −271 (−78.3% P- HR = 211d 0.0177 6225219- NA R60H STATES/ 2 ITT: vs improve- value = 432481- vs 0.678 CANADA vs 0.9% 346d ment) 0.0269 90.876 NAd (0-Inf) 4 (0-Inf) B_D PSMB9/ A/A Clinical REGION UNITED Excluded 6 536 133 N: % in 414d 76 (22.5% P- HR = NAd 0.9831 1.004 NA R60H STATES/ 264 ITT: vs improve- value = 0.814 vs (0.711- CANADA vs 79.4% 338d ment) 0.052 (0.661- NAd 1.418) 272 1.002) B_D PSMB9/ A/A Clinical REGION UNITED Total 6 536 133 N: % in 414d 69 (20% P- HR = NAd 0.8540 1.033 NA R60H STATES/ 266 ITT: vs improve- value = 0.828 vs (0.734- CANADA vs 80.3% 345d ment) 0.0744 (0.673- NAd 1.453) 276 1.019) 

The invention claimed is:
 1. A method for predicting response to a cancer treatment comprising bortezomib and rituximab in a non-Hodgkin's lymphoma cancer patient, comprising: detecting the presence of a first predictor in a biological sample from said non-Hodgkin's lymphoma cancer patient, wherein said first predictor is low CD68; detecting the presence of a second predictor in said non-Hodgkin's lymphoma cancer patient, wherein said second predictor is a PSMB1 (P11A) polymorphism comprising a C/G heterozygote; wherein the presence of a biomarker pair comprising the low CD68 and the PSMB1 (P11A) polymorphism is correlated with at least one positive outcome; and selecting the non-Hodgkin's lymphoma cancer patients that have an increased chance for a favorable outcome to the cancer treatment comprising bortezomib and rituximab based on the presence of the biomarker pair comprising the first and second predictor; and treating the selected non-Hodgkin's lymphoma cancer patients with the cancer treatment comprising bortezomib and rituximab.
 2. The method of claim 1, wherein low CD68 is 50% or less CD68-positive cells, as determined by immunohistochemistry.
 3. The method of claim 1, wherein the non-Hodgkin lymphoma is follicular B-cell non-Hodgkin lymphoma. 